Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1B(O)O>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[C:40]([Cl:39])[CH:41]=[CH:42][C:43]=2[Cl:46])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3Cl)sc2N)c1N1CCC(CN)CC1
Yield: 19 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 2,5-dichlorobenzeneboronic acid gave 277 as an off-white solid (19 mg, 19%). 1H NMR (400 MHz, d4-MeOD) δ 8.39 (d, J=2.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.48 (s, 1H), 7.37 (dd, J=8.6, 2.6 Hz, 1H), 3.73 (s, 3H), 3.24-3.11 (m, 4H), 2.60 (d, J=6.6 Hz, 2H), 1.85 (d, J=12.5 Hz, 2H), 1.55-1.44 (m, 1H), 1.36 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Product: Cc1cccc(C(=O)O)c1Nc1ccnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinoline and 2-amino-3-methyl benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-chloro-4-quinolylamino)-3-methyl benzoic acid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=3[CH:20]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:28]=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]2[CH:35]=1.C(OCC)(=O)C>C1COCC1>[N:28]1[C:27]([CH2:26][N:15]2[C:14](=[O:19])[C:13]3[CH:20]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=4)[CH:10]=[CH:11][C:12]=3[O:18][CH2:17][CH2:16]2)=[CH:35][N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=12
Reactant: O=C1NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Reactant: ClCc1cn2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCCN1Cc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (50 mg) was dissolved in dry THF and the NaH suspension (6 mg, 60% in oil) was added, followed shortly by 2-(chloromethyl)imidazo[1,2-a]pyridine (29 mg) and stirred overnight at room temperature. Worked up with ethyl acetate and pH 7 buffer organic layer dried over MgS(O)4 and concentrated. Purification was conducted on normal phase (CH2Cl2/10% EtOH in ethyl acetate gradient) followed by reverse-phase (ACN/H2O, 0.1% TFA). Resulting glassy solid was dissolved in dioxane, diluted 10-fold with 0.1N HCl and lyophilized resulting in 4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one hydrochloride salt as a white solid (42.2 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14](C)[CH2:15]CO.C([Sn](=O)CCCC)CCC>>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH2:8][N:14]([CH3:15])[CH3:13])=[O:5]
Reactant: CN(C)CCO
Reactant: CCOC(=O)C1CCCCN1C
Agent: CCCC[Sn](=O)CCCC
Product: CN(C)CCOC(=O)C1CCCCN1C
Temperature: 145 °C

Procedure:
A mixture of 85 g (0.5 mol) of ethyl 1-methylpipecolinate, 44.6 g (0.5 mol) of N,N-dimethylethanolamine and 0.82 g of dibutyltin oxide was heated at about 145° C. for 30 hours. The ethanol by-product was collected in a Dean-Stark trap. When the rate of ethanol evolution and amount of ethanol collected showed that the reaction was essentially complete, the reaction was heated at about 180° C. until ethanol evolution ceased. The liquid product was purified by distillation at reduced pressure to provide 2-(N,N-dimethylamino)ethyl N-methylpipecolinate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[CH:21][CH:22]=1.Cl>COCCO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:17]=[C:18]3[NH:19][N:20]=[CH:21][C:22]=23)=[CH:4][CH:3]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Agent: Cl
Solvent: COCCO
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 47.2 %

Procedure:
In a volumetric flask, 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (23.56 g, 109.4 mmol, obtained in reference example 1) and 2-methoxyethanol (150 mL) were introduced. A solution of 3-amino-2H-pyrazole (10.00 g, 120.3 mmol) in 2-methoxyethanol (170 mL) and 37% HCl (3.23 g, 32.8 mmol) were added under argon atmosphere. This was heated to reflux for 3 days. It was allowed to cool and concentrated. The solid obtained was dissolved in CHCl3 (400 mL) and MeOH (50 mL) and washed with 0.1 N HCl (300 mL) and 1 N NaOH (300 mL). The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 9.93 g of the desired product in solid cream form (yield: 47%)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:21]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18])[C:29](=[O:30])[O:31][CH3:32]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-nitrobenzyl)amine from Step C (0.47 g, 1.0 mmol) in methylene chloride (20 ml) at room temperature, methyl chloroformate (0.12 ml, 1.54 mmol) and triethylamine (0.29 ml, 2.05 mmol) were added. The solution was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using 1:9 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.11 (m, 1H), 8.02 (dd, J=9.0, 2.5 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 4.67 (m, 4H), 3.89 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[C:34](Cl)([CH3:36])=[O:35]>C(Cl)Cl.O>[C:34]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:26])=[O:27])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1)(=[O:35])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCNCC4)c3n2)c1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
To a solution of N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.082 g, 0.177 mmol) in DCM (0.886 ml) was added TEA (0.062 ml, 0.443 mmol) at room temperature. After stirring for 2 hours at room temperature, AcCl (0.019 ml, 0.266 mmol) was added to the mixture at 0° C. After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep TLC (DCM:MeOH=20:1) to give N-(5-(4-(1-acetylpiperidin-4-yloxy)-pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.007 g, 7%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.05-2.18 (2H, m), 2.19 (3H, s), 3.53-3.59 (2H, m), 3.65-3.76 (2H, m), 3.89-3.40 (2H, m), 5.74-8.79 (1H, m), 7.44-7.48 (2H, m), 7.53-7.57 (1H, m), 7.86-7.89 (2H, m), 8.23 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.46 (1H, d, J=2.8 Hz), 8.53 (1H, d, J=2.4 Hz), 8.84 (1H, s), 9.12 (1H, d, J=1.6 Hz). m/z=505.1 [M+1]+.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[N:19]([CH2:22][CH2:23][NH2:24])=[N+:20]=[N-:21].C(N(CC)CC)C>ClCCl>[N:19]([CH2:22][CH2:23][NH:24][C:3](=[O:5])/[C:2](/[CH3:1])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NCCN
Reactant: C/C(=C\c1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(=C\c1ccccc1)C(=O)NCCN=[N+]=[N-]
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added (E)-2-methyl-3-phenylacrylic acid (0.0.512 g, 3.15 mmol) and dichloromethane (10 mL). Oxalyl chloride (0.400 g, 3.15 mmol) was added dropwise to the reaction mixture and allowed to stir for one hour. Then, the reaction mixture was concentrated de vacuo. To the crude mixture was then added dichloromethane (10 mL), 2-azidoethanamine (0.299 g, 3.47 mmol) and then triethylamine (0.351 g, 3.47 mmol) and allowed to stir for two hours. The reaction mixture was then concentrated de vacuo and then purified via silica gel column chromatography (100% dichloromethane to 1:40 methanol:dichloromethane) to give (E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.698 g, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.39 (m, 6H), δ 7.01 (s, 1H), δ 3.51 (t, 2H), δ 3.45 (t, 2H), δ 2.13 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.5, 136.2, 134.5, 132.0, 130.3, 129.6, 128.9, 128.6, 128.3, 50.9, 39.8, 14.5 ppm; HRMS (ESI) calcd for C12H14N4O (M+) 230.1168, found 230.1165.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:18][CH:19]=[CH2:20])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: C=CCN
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: C=CCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), prop-2-en-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 0.4), 141 (9), 95 (8), 75 (8), 71 (6), 70 (bp).
Reaction SMILES: [F:1][C:2]1[C:11](S(C(F)(F)F)(=O)=O)=[C:10]([F:19])[C:9]([F:20])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>O1CCOCC1.CCOCC>[CH:21]([C:11]1[C:2]([F:1])=[C:3]([CH:8]=[C:9]([F:20])[C:10]=1[F:19])[C:4]([OH:6])=[O:5])=[CH2:22]
Reactant: COC(=O)c1cc(F)c(F)c(S(=O)(=O)C(F)(F)F)c1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 98 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 2,4,5-trifluoro-3-trifluoro methanesulfonyl benzoic acid, methyl ester (22.0 g, 0.065 mol) in dioxane (100 mL) was added tri-n-butyl vinyl tin (21.6 g, 0.068 mol), lithium chloride (16.7 g, 0.37 mL) 2,6-di-t-butyl-4-methylphenol (0.08 g) and palladium-tetra-triphenyl phosphine (1.1 g). The mixture was heated at 98° C. for 12 hours, cooled, diluted with ether and filtered through celite. The ether layer was concentrated and the resulting residue suspended in hexane and filtered. The filtrate was concentrated to a yellow oil which was immediately dissolved in methanol (250 mL) and 1 N sodium hydroxide (150 mL). The mixture was stirred at room temperature for 4 hours, diluted with water and ether. The aqueous layer was acidified (pH ~2) with 6 N HCl and extracted with methylene chloride. The organic layer was dried and concentrated to provide the desired product (9.6 g, 77%); mp 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:30][CH2:31][O-].[Na+]>C(O)C>[CH2:30]([C:16]1[N:15]([C:11]2[C:12]([F:14])=[CH:13][C:2]([Cl:1])=[C:3]([CH:10]=2)[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5])[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:24])([F:26])[F:25])[N:17]=1)[CH3:31]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained isopropyl 5-[2-ethyl-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-2-chloro- 4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.83 ppm (d,1H), 7.39 ppm (d,1H), 6.65 ppm (s,1H), 5.72 ppm (m,1H), 4.48 ppm (m,2H), 1.38 ppm (d,3H), 1.37 ppm (d,3H), 1.29 ppm (t,3H);
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>C(O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:1][N:2]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: CC(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CC(C)c1ccc(C=NNc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 90 °C
Yield: 62.8 %

Procedure:
In 50 ml of ethanol were dispersed 3.03 g of 2-hydrazino-5-nitropyridine and 3.08 g of 4-isopropylbenzaldehyde. The dispersion was refluxed at 90° C. for one hour. The reaction solution was allowed to cool at room temperature and further cooled down to 5° to 10° C. to cause crystals to fully precipitate, which were collected by suction filtration. The crystals were washed with a small amount of ethanol and dried in vacuum at 60° C. for 1.5 hours, obtaining 3.51 g (yield 62%) of dark yellow acicular crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:18]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5ccn(CCc6ccccc6)n5)c4c3)cc2F)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2cnc3[nH]cc(-c4ccn(CCc5ccccc5)n4)c3c2)ccc1C1CCNCC1
Yield: 42.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (66 mg, 0.116 mmol) was deprotected in TFA/toluene (5/5 mL) to afford 23 mg (34% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.82-8.81 (d, 1H), 8.58 (s, 1H), 7.87 (s, 1H), 7.58-7.45 (m, 4H), 7.23-7.11 (m, 5H), 6.577-6.570 (d, 1H), 4.48-4.44 (t, 2H), 3.56-3.52 (d, 2H), 3.24-3.15 (m, 5H), 2.15-2.03 (m, 4H). MS: m/z=466.5 (M+1), HPLC: 96.98% in method A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(CCCNCCCc2cccc(Cl)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CCCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 115.5 %

Procedure:
To a solution of 3-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-benzoic Acid methyl ester (50.3 mg, 0.145 mmol) and triethylamine (32.4 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (18.3 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and was diluted with CH2Cl2. The organic solution was washed consecutively with aqueous HCl (5.5%, 1×), H2O (1×), NaHCO3 (1×) and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title product of Step A as an oil (71 mg). MS 424 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl-].[In+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([CH:23]1[CH2:25][CH:24]1[C:26]#[N:27])(O)[CH3:21].[CH3:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([CH:23]1[CH2:25][CH:24]1[C:26]#[N:27])([C:36]1[C:35]2[C:39](=[C:31]([CH2:30][S:29][CH3:28])[CH:32]=[CH:33][CH:34]=2)[NH:38][CH:37]=1)[CH3:21]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
0.08 ml (1.08 mmol) of trifluoroacetic acid and 218 mg (0.99 mmol) of indium(III) chloride were added to 200 mg (0.90 mmol) of the compound from Example 133A and 318 mg (1.79 mmol) of the compound from Example 8A in 8 ml of dichloromethane at RT, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 128 mg (37% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13]4)[CH:7]=2)[O:2]1.C1OC2C=CC(B(O)O)=CC=2O1.[Br-:37].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:37][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13]3)[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12
Reactant: [Br-]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)OCO4)ccc2c1
Agent: OB(O)c1ccc2c(c1)OCO2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(-c3cc(Br)c4c(c3)OCO4)ccc2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of ethyl 6-[4,5-methylenedioxyphenyl]-2-naphthoate (19.61 g, 56.50 mmol, prepared in a similar manner via a Suzuki coupling of 3,4-methylenedioxyphenyl boronic acid and 6-carboethoxynaphthyl-2-trifluoromethanesulfonate, 84% yield) in CH2Cl2 (900 mL) was pyridinium tribromide (19.91 g, 62.26 mmol) at RT. The resulting mixture was allowed to stir overnight. After 24 hours, additional amount of pyridinium tribromide (9.05 g, 28.3 mmol) was added and the mixture stirred overnight. The mixture was washed with H2O, brine and dried over magnesium sulfate. After filtering, the solvent was removed and purified on silica gel (CH2Cl2) to give ethyl 6-[3-bromo-4,5-methylenedioxyphenyl]-2-naphthoate (100%) as a white solid. 1H NMR (300 MHz; CDCl3): δ 1.47 (t, J=7.2 Hz, 3H), 4.46 (q, J=7.2 Hz, 2H), 6.05 (s, 2H), 6.90 (s, 1H), 7.15 (s, 1H), 7.57 (dd, J1=9.0 Hz, J2=1.5 Hz, 1H), 7.84 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: [C:1]([S:5]([NH:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:20]([C:11]1[S:10][C:9]([NH:8][S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:6])=[CH:13][CH:12]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)S(=O)(=O)Nc1cccs1
Reactant: CCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(NS(=O)(=O)C(C)(C)C)s1
Temperature: -20 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(t-butylsulfonamido)thiophene (3.42 g, 15.6 mmol) in anhydrous THF cooled to -78° C. under N2 was added 2.5M n-BuLi (15.6 mL, 2.5 equiv). The reaction was warmed to -20° C. over 3.5 h. After stirring at -20° C. for an addional h, iodopentane (2.4 mL, 1.2 equiv) was added. The ice bath was removed and the reaction was stirred at rt overnight. The next day the reaction was quenched with sat'd NH4Cl solution and the THF was removed in vacuo. The residue was extracted with Et2O/EtOAc and washed with water and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc (15:1). Removal of the solvent afforded 2.72 g (60%) of the titled compound as a yellow oil. Rf=0.4 (6:1 Hex/EtOAc).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH:9]([OH:12])CO.O1CCC(OCC2CC[N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=4)[N:32]=3)[CH2:23][CH2:22]2)CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:38][C:36]([F:37])([F:39])[C:33]1[N:31]2[N:32]=[C:27]([N:24]3[CH2:5][CH2:6][CH:7]([CH2:8][O:3][CH2:4][CH2:9][OH:12])[CH2:22][CH2:23]3)[CH:28]=[CH:29][C:30]2=[N:35][N:34]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(COC4CCOCC4)CC3)nn12
Reactant: OCC(O)C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCOCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.180 g, 4.5 mmol) was added to neat tetrahydropyranylethyleneglycol (3 g, 20.5 mmol). When the effervescence had subsided 6-[4-(methanesulfonyloxymethyl)piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 294, preparation of starting materials) (1.138 g, 3 mmol) was added and the mixture was heated at 100° C. for 40 minutes. The reaction mixture was partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. The crude intermediate was disolved in methanol (20 mL) and p-toluenesulfonic acid monohydrate (0.855 g, 4.5 mmol) was added. The solution was stirred for 1 hour and then evaporated. The reaction mixture was partitioned between DCM and water and the organic phase was washed with water and brine, dried over MgSO4 and evaporated. The product was isolated by MPLC silica chromatography, eluting with 5% methanol/DCM. The product containing fractions were evaporated giving a crystalline solid which was triturated with ether, giving 2-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]ethanol (0.563 g, 54%)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][C:27]([F:26])([F:37])[F:38])=[CH:30][CH:31]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:24][CH:25]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)Oc1ccc(CCNc2ncc(CC)cn2)cc1
Product: CCc1cnc(N(CCc2ccc(OC(C)C(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
In a two-step sequence similar to the previous example, alkylation of the above intermediate ethyl 2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoate with 4-trifluoromethoxy-benzylbromide (1 eq) (1.5 eq NaH; 80C) followed by hydrolysis of the intermediate ester afforded the title compound.