Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.C(OC(=O)[NH:25][C:26]([CH3:34])([CH3:33])[CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:25][C:26]([CH3:34])([CH3:33])[CH2:27][C:28]1[S:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(Cc1cccs1)NC(=O)OC(C)(C)C
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(N)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and (1,1-Dimethyl-2-thiophen-2-yl-ethyl)-carbamic acid tert-butyl ester (prepared by BOC protection of 1,1-Dimethyl-2-thiophen-2-yl-ethylamine), followed by BOC cleavage with HCl in dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccccn3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]([OH:17])=[O:16]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: OCCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)COCCc1cccc(F)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 63.2 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-ethanol (4.0 g, 28.5 mmol) in DMF (60 ml) was added a 60% dispersion of sodium hydride in oil (2.40 g, 60 mmol). The suspension was heated to 60° C. for 0.75 hours. Chloroacetic acid (4.72 g, 50 mmol) was added dropwise. After 36 hours at 60° C. the brown reaction mixture was brought to dryness under reduced pressure, dissolved in EtOAc and washed with 1M HCl, water and brine. The organic layers were dried over MgSO4, filtrated, the solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, EtOAc/heptane, 3/1) to yield [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (2.02 g, 18 mmol; 36%) as colorless liquid. MS (m/e): 197.4 [M−H]−.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[O:20][C:21]([C:24]3[S:25][C:26]([CH:30]=O)=[C:27]([CH3:29])[CH:28]=3)=[N:22][N:23]=2)[CH:16]=[C:15]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH2:30][C:26]1[S:25][C:24]([C:21]2[O:20][C:19]([C:17]3[CH:16]=[C:15]([CH3:32])[C:4]([O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH2:1][CH3:2])[CH:18]=3)=[N:23][N:22]=2)=[CH:28][C:27]=1[CH3:29])[CH3:35]
Reactant: CNC
Reactant: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)o2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(-c2nnc(-c3cc(C)c(CN(C)C)s3)o2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 31.5 %

Procedure:
The title compound (4 mg) is prepared starting from N-((2S)-3-{2-ethyl-4-[5-(5-formyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (12 mg, 26 μmol) and dimethylamine (14 mg, 105 μmol) according to Method C; LC-MS*: tR=0.80 min; [M+1]+=488.95; 1H NMR (D6-DMSO): δ1.23 (t, J=7.5 Hz, 3H), 2.23 (s, 3H), 2.26 (s, 6H), 2.35 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 3.21-3.29 (m, 1H), 3.39-3.47 (m, 1H), 3.61 (s, 2H), 3.71-3.81 (m, 2H), 3.84 (d, J=3.3 Hz, 2H), 3.93-4.00 (m, 1H), 5.31 (d, J=5.3 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.68-7.72 (m, 2H), 7.77 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and methanesulfonyl chloride (40 mg, 0.35 mL) at ice-bath. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 365.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[OH:9])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2O)CC1
Reaction time: 18 h
Yield: 82 %

Procedure:
2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231 mmol) were set stirring in dichloromethane (600 mL). Sodium triacetoxyborohydride (58.0 g, 274 mmol) was added in portions over 10 min. Acetic acid (12 mL, 210 mmol) was then added and the mixture left to stir for 18 h. Saturated NaHCO3 was added and the organics seperated. The organics were dried (MgSO4) and evaporated to give 56 g (82%) of a light beige solid. TLC (silica, 50% EtOAc/hexanes): Rf=0.66. MS (electrospray): exact mass calculated for C16H23ClN2O3, 326.14. m/z found, 349.1 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 6.70 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.55-3.50 (m, 1H), 2.93 (br s, 2H), 1.93 (d, J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35 (d, J=11.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH:24][C:35]([NH:34][C:32]4[N:31]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=4)=[O:36])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(N)nc34)c3ccccc23)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 2-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly pink solid (70 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[BH4-].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(O)ccc1Cl
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(Cl)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a mixture of 2-chloro-5-hydroxybenzaldehyde (200 mg, 1.27 mmol, intermediate 28a) and morpholine (280 mg, 3.21 mmol) in methanol (10 mL) was added 2 drops of acetic acid and the mixture was stirred at room temperature for 2 h. To the mixture, sodium borohydride (97 mg, 2.56 mmol) was added and the resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with dilute hydrochloride acid and concentrated to give crude product. This crude material was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to give 4-chloro-3-(morpholinomethyl)phenol (150 mg, 51.8% yield) as white solid. LCMS retention time 0.378; LCMS MH+ 228.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21]O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:41])=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21][Cl:41])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCO)Cc1cccc(CC(=O)OC)c1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (viii) (2.43 g) and thionyl chloride (10 mL) in DCM (30 mL) was stirred at rt for 4 h then evaporated under reduced pressure to give the subtitle compound. Used crude in next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([CH:10]2[CH:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:14][CH2:13][CH2:12][NH:11]2)=O)[CH2:4][CH2:3]1.FC(F)(F)S(O)(=O)=O>>[F:24][C:20]1[CH:21]=[CH:22][C:23]2[C:8](=[C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[CH2:16][CH2:17][C:18]=2[CH:19]=1
Reactant: CN1CCC(C(=O)C2NCCCC2CCc2cccc(F)c2)CC1
Agent: O=S(=O)(O)C(F)(F)F
Product: CN1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Yield: 38 %

Procedure:
A solution of (1-methyl-4-piperidinyl)[3-[2-(3fluorophenyl)ethyl]-2-piperidinyl)methanone (15.0 g, 0.046 mole) in 74 mL (125.5 g, 0.837 mole) of trifluoromethanesulfonic acid is stirred at ambient temperature for 18 hours. The reaction is quenched with ice-water and the solution made basic with potassium hydroxide. The product is extracted into ethyl acetate. The ethyl acetate solution is filtered to remove insolubles and the filtrate is concentrated to a residue. Following purification by silica gel chromatography, 5.4 o (0.0175 mole) of oroduct is obtained in 38% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[N:14]=[N:13]1)[C:9](O)=[O:10].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH3:52]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[N:14]=[N:13]1)[C:9]([NH2:52])=[O:10]
Reactant: O=C(O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Reactant: N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 mg (0.045 mmol) of the compound from Example 104 were initially charged in 1 ml of DMF, and 9 mg (0.058 mmol) of HOBt and 11 mg (0.058 mmol) of EDC were added. After 10 min of stirring at RT, 0.5 ml (0.90 mmol) of ammonia solution (35% strength in water) was added, and the reaction was stirred at RT for 16 h. The reaction mixture was then purified directly, without any further work-up, by chromatography [Method 19]. This gave 10 mg (40% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (90.0 mg, 0.132 mmol), phenylboronic acid (80.5 mg, 0.660 mmol), Pd(PPh)3Cl2 (4.60 mg, 0.0065 mmol), 2 M Na2CO3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.6 mL) and DME (2.4 mL). Purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid) afforded the product (33.7 mg, 38%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:34]3[N:39]=[C:38]([C:40]4[C:41]([C:49]5[CH:50]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]6[S:59][CH:60]=[CH:61][CH:62]=6)[CH:52]=[CH:53][CH:54]=5)=[N:42][N:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=45)[CH:37]=[CH:36][N:35]=3)C=CC=2)=CN=C1>CC(O)C.Cl.CCOC(C)=O>[F:13][C:11]([F:14])([F:12])[C:10]([N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]2[N:39]=[C:38]([C:40]3[C:41]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]5[S:59][CH:60]=[CH:61][CH:62]=5)[CH:50]=4)=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)[CH:3]=1)=[O:15]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: CS(=O)(=O)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Temperature: 180 °C
Yield: 63 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]acetamide (68 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 2 drops of 12 N HCl and heated in a microwave for 15 min. at 180° C. The reaction mixture was then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 7.67-7.80 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.26-7.39 (m, 4H), 7.17 (t, J=7.7 Hz, 1H), 7.05 (s, 1H), 6.94 (t, J=6.9 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.62-6.64 (m, 2H), 6.53 (s, 1H), 4.68 (s, 2H), 3.96 (s, 2H), 3.72-3.75 (m, 2H), 3.16-3.24 (m, 2H), 2.90 (s, 3H). ES-LC/MS m/z=734 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:15]=[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]3=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: FCc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 37.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (111 mg, 0.58 mmol, Example 190(E)) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 61 mg (0.22 mmol, 37%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:42](=[O:44])[CH:41]([C:31]2[CH:32]=[CH:33][C:34]([N:35]3[C:39]([CH3:40])=[N:38][N:37]=[N:36]3)=[C:29]([Cl:28])[CH:30]=2)[CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (prepared in Example 3, 151 mg, 0.45 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (234 mg, 1.35 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionamide (90 mg, 42%) as an amorphous white solid: EI-HRMS m/e calcd for C21H22BrClN6O (M+) 489.0727, found 489.0727.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[C:11]1([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]2[N:18]=[CH:19][N:20]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: c1ccc(-c2c[nH]cn2)cc1
Product: c1ccc(-c2cn(-c3ccnc4[nH]ccc34)cn2)cc1
Yield: 291 %

Procedure:
A melt of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-phenyl-1H-imidazole (0.24 g, 0.0016 mol) was heated at 200° C. overnight. The reaction was partitioned between ethyl acetate and saturated NaHCO3, separated and the organic phase was washed with brine. The organic layer was then dried and evaporated to give 250 mg of an orange oil. The oil was chromatographed with 7% MeOH/DCM, 0.7% NH4OH, sample in solvent system. Collected 74 mg of the product as an orange glass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of a brown solid which was dried at 60° C. for 4 h to afford the desired product (50 mg, 59 yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][CH:28]=[CH2:27])=[CH:8][CH:7]=1
Reactant: C=CCBr
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(OCC=C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 92.1 %

Procedure:
To a solution of 18 (30 g, 107.4 mmol, 1.0 equiv) in DMF (170 mL) at room temperature was added solid K2CO3 (29.6 g, 214.2 mmol, 2.0 equiv) then allylbromide (10.2 mL, 116.3 mmol, 1.1 equiv) dropwise. The suspension was stirred at room temperature for 9 hours, after which time water (500 mL) was added and extracted with ether (4×250 mL). The organics were combined, washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (20→60% EtOAc/hexane) afforded 19 (31.6 g, 92%) as a clear oil. Rf=0.27 (25% EtOAc/hexane); FTIR (neat, cm−1) 3343, 2919, 1721, 1510, 1239, 1215, 1176, 1052, 1017; 1H NMR (400 MHz, CDCl3) δ7.00 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.99 (m, 1H), 5.85 (m, 1H), 5.44 (d, J=8.0 Hz, 1H), 5.36 (dd, J=17.4, 1.2 Hz, 1H), 5.25 (s, 1H), 5.22 (dd, J=10.2, 1.6 Hz, 1H), 5.15 (dd, J=10.4, 1.2 Hz, 1H), 4.56 (dd, J=14.2, 6.0 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.45 (d, J=5.2 Hz, 2H), 3.66 (s, 3H), 3.03 (dd, J=14.4, 5.2 Hz, 1H), 2.96 (dd, J=14.0, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ172.0, 157.5, 155.4, 133.1, 132.5, 130.0, 127.8, 117.4, 117.3, 114.5, 68.4, 65.5, 54.7, 52.0, 37.0; MS (ES+) calculated for C17H21NO5 (M+H)+: 320.1420, found: 320.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N(C)CCCN(C)C)c1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 1.44-1.58 (m, 2H), 2.06 (s, 6H), 2.15 (t, 2H), 2.21 (s, 3H), 2.69 (s, 3H), 3.02 (t, 2H), 3.48-3.53 (m, 4H) 3.69-3.73 (m, 4H), 7.1 (d, 1H), 7.19-7.25 (m, 2H), 7.44-7.62 (m, 3H), 7.74-7.64 (m, 1H), 7.94 (d, 1H), 8.26 (d, 1H), 10.13 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 576.