Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>ClC(Cl)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CCC(N3CCc4ccccc4C3)CC2)cc1

Procedure:
1,2,3,4-Tetrahydroisoquinoline (700 mg, 5.3 mmol), acetic acid (3.2 g, 5.3 mmol), sodium triacetoxyborohydride (2.2 g, 11 mmol) and benzylpiperidone (1.0 g, 5.3 mmol) were stirred at room temperature for 3.5 hours in dichloroethane (7 ml). The reaction solution was alkalified by adding sodium hydroxide aqueous solution, the reaction product was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 900 mg (3.0 mmol, 56% in yield) of the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][CH:5]=[O:6].[OH:11]OS([O-])=O.[K+]>CN(C)C=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][C:5]([OH:11])=[O:6]
Reactant: CCC(CF)(CF)CC=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CF)(CF)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3,3-bis(fluoromethyl)pentanal (6.8 g, 45 mmol) and Oxone® (27.9 g, 45 mmol) in N,N-dimethylformamide (120 mL) was stirred at rt for 4 h. The reaction was quenched with 2N hydrochloric acid (200 mL) and extracted with ethyl acetate (4×100 mL). The extracts were washed with 2 N hydrochloric acid (150 mL) and 5% aqueous lithium chloride (150 mL), dried over sodium sulfate and concentrated to give 3,3-bis(fluoromethyl)pentanoic acid.
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17](S(C)(=O)=O)=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1.[OH-].[Na+].C(O)(=[O:29])C>O1CCCC1.O>[F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17]([OH:29])=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1
Reactant: CC(=O)O
Reactant: CS(=O)(=O)c1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Temperature: 60 °C
Yield: 91.7 %

Procedure:
7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (0.410 g) was suspended in Tetrahydrofuran (2.00 mL), 5.0 M of Sodium hydroxide in Water (1.00 mL, 5.00 mmol) was added and the mixture was heated in a vial, in a block at 60° C. for 3 h. The mixture was then treated with a solution of Acetic acid (0.500 mL, 8.79 mmol) in Water (5.50 mL), generating an orange ppt. The mixture was cooled, the solids collected, washing with 10 mL water. Dry on the Buchner to afford 7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.310 g; Yield=78.6%). LCMS (HPLC): 0.97 min, m/z=292 (M+H); 1H-NMR (DMSO-d6): 11.97 (s, 1H), 9.10 (s, 1H), 8.38 (d, 1H, 8.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 7.38 (m, 1H), 7.25 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=4.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccccc1Oc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccccc1Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Methyl 2-(2-aminophenoxy)benzoate (9.2 g, 0.038 mol) and sodium hydroxide (3.2 g, 0.08 mol) in 1:1 methanol/water (200 mL) was stirred under argon at room temperature for 3 h. The methanol was evaporated, the aqueous residue was acidified with dilute HCl, extracted with ethyl acetate, dried over anhydrous MgSO4, filtered, and evaporated to give the crude product which was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid), and then recrystallized from ethyl acetate/hexane to give the title compound as a white crystalline solid; mp 150°-151° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:27][C:28]1[N:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[S:31][C:32]=1[CH:33]=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>O1CCCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH:16]=[CH:33][C:32]2[S:31][C:30]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)=[N:29][C:28]=2[CH3:27])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[4-(benzyloxy)-3-methylphenyl]ethanone (intermediate 8, 1.15 g) in dry tetrahydrofuran (15 ml) at −78° C. was treated dropwise with lithium diisopropylamide (2.6 ml of 2M solution in heptane/tetrahydrofuran/ethylbenzene) under nitrogen. The reaction mixture was warmed to 0° C. for 30 minutes. The mixture was cooled to −78° C. and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (intermediate 2, 1.08 g) in dry tetrahydrofuran (15 ml) was added drop-wise at −78° C. and the reaction mixture stirred at 21° C. for 2 hours. Acetic acid (4 ml) in dry tetrahydrofuran (4 ml) was added followed by toluenesulphonic acid (0.1 g) and the reaction mixture was heated at 50° C. for 1 hour and then concentrated. The residue was partitioned between saturated bicarbonate solution and ethyl acetate; the aqueous layer separated and extracted thrice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash chromatography using cyclohexane:ethyl acetate (6:1) as eluent to give the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[N:20]=[C:2]([NH:21][C:22]3[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:27])=[CH:24][C:23]=3[O:38][CH3:39])[N:3]=[CH:4][C:5]1=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC(C)CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCC(C)C)CC(C)C(=O)N2C
Yield: 55 %

Procedure:
A solution of 0.05 g, (0.00017 mole) of (rac)-2-chloro-5,7-dimethyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-27), 0.044 g, (0.00017 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.049 g, (0.00026 mole) of p-toluenesulfonic acid monohydrate and 4 mL of 2-propanol was heated at 180 degree for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25) to give 0.049 g of (rac)-4-[5,7-dimethyl-9-(3-methyl-butyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-27). HRMS (ES+) m/z Calcd for C28H41N7O2+H [(M+H)+]: 524.3344. Found: 524.3342.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][N:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1.[CH3:12]I.O>CN(C)C=O>[Br:3][C:4]1[N:8]([CH3:12])[N:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1
Reactant: O=[N+]([O-])c1n[nH]c(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc([N+](=O)[O-])nc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
1.1 g (28.5 mmol) of 60% sodium hydride are added to a solution of 5 g (25.9 mmol) of 5-bromo-3-nitro-1H-[1,2,4]triazole in 80 ml of dimethylformamide, cooled beforehand to 0° C. The reaction medium is stirred for 20 minutes and 8 ml (129.5 mmol) of methyl iodide are then added. After stirring at room temperature for 18 hours, water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed thoroughly with water, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 75/25 heptane/ethyl acetate mixture. 3.2 g (60%) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](OC)=[O:24])=[CH:14][C:12]=2[N:13]=1.[CH:28]1([C:31]2[CH:32]=[CH:33][C:34]([F:38])=[C:35]([CH:37]=2)[NH2:36])[CH2:30][CH2:29]1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:28]1([C:31]2[CH:32]=[CH:33][C:34]([F:38])=[C:35]([NH:36][C:23]([C:15]3[C:16]4[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=4[C:11]4[NH:10][C:9]([NH:8][C:7]5[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=5[Cl:27])=[N:13][C:12]=4[CH:14]=3)=[O:24])[CH:37]=2)[CH2:30][CH2:29]1
Reactant: Nc1cc(C2CC2)ccc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C4CC4)ccc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 58.2 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 5-cyclopropyl-2-fluoroaniline (0.053 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 0.62 (d, J=6.3 Hz, 2H), 0.95 (d, J=8.4 Hz, 2H), 1.55 (s, 6H), 1.91 (m, 1H), 3.09 (s, 2H), 6.82 (m, 1H), 7.17 (t, J=10.5 Hz, 1H), 7.30 (s, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.45 (s, 2H), 9.95 (s, 1H), 10.99 (s, 1H), 11.56 (br s, 1H); MS [M+H]+: 526.12.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:60]OS(C)(=O)=O)[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:60][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 79.3 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 171.7 %

Procedure:
A mixture of 3.4 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.5 g of 2-(dimethylamino)ethyl chloride hydrochloride, 3.23 g of potassium carbonate and 80 ml of acetone is treated in the same manner as described in Example 1. The product thus obtained is converted into its hydrochloride and recrystallized from a mixture of acetone and ethanol. 3.75 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([CH:10]=O)=[N:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:13]([C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:14]>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:13][N:14]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NNc1cccnn1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2cccnn12

Procedure:
4 g. lead tetraacetate were suspended in 40 ml. glacial acetic acid, 1.5 g. of the hydrazone obtained from 1.55 g. 5-nitro-1-methyl-imidazole-2-aldehyde and 1.1 g. 3-hydrazinopyridazine hydrochloride (prepared by heating for 30 minutes in 20 ml. 50% aqueous methanol at 50° C. and subsequent neutralization with sodium acetate) were added, while stirring at 50° - 60° C., the reaction mixture further stirred for 15 minutes, considerably evaporated in a vacuum, the resultant crystals filtered off with suction, triturated with water and dried for 2 hours in a vacuum at 120° C., 1.05 g. of the desired 3-(5-nitro-1-methyl-2 -imidazolyl)-s-triazolo[4,3-b]pyridazine being obtained, which has a melting point of 235° - 237° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methyl-pyridin-2-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M142) (244 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (168 mg, 87%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)=[O:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)Cl>[CH:17]12[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:19]3)[CH:10]1[NH:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:31])[O:32][CH3:33])[CH2:3]1)=[O:8])[CH2:18]2
Reactant: N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 49.1 %

Procedure:
A vial equipped with a flea stir bar was charged with (R)-3-amino-N-(2-adamantyl)pyrrolidine-1-carboxamide (25 mg, 0.095 mmol), i-Pr2NEt (0.07 mL, 0.38 mmol) and CH2Cl2. The solution was stirred and methyl chloroformate (0.009 mL, 0.11 mmol) was added. The mixture was stirred overnight at rt and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (R)-methyl 1-(2-adamantylcarbamoyl)pyrrolidin-3-ylcarbamate (15 mg, 49%). LC-MS Method 1, tR=1.5 min, m/z=322; 1H NMR (CDCl3) 1.60-2.00 (15H), 2.20 (m, 1H), 3.26 (m, 1H), 3.46 (m, 2H), 3.63 (m, 1H), 3.69 (s, 3H), 3.96 (s, 1H), 4.30 (1H), 4.60 (1H), 4.89 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenylboronic acid (2.2 g, 8.5 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.79 g, 10.2 mmol), Pd(PPh3)2Cl2(179 mg, 0.26 mmol), K2CO3 (2.35 g, 17 mmol), and Cu2O (37 mg, 0.26 mmol) in THF (6 mL) and H2O (3 mL) in a tube sealed under N2 was heated at 80° C. for 4 h, cooled to rt and partitioned between EA and water, extracted with EA (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE to afford 1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.5 g, yield 55%) as oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Reactant: CCCCN
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1c2cnn1CC
Reaction time: 12 h

Procedure:
5.7 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol) are dissolved in 50 ml of dry alcohol. After addition of 1.5 g of n-butylamine, the mixture is heated at reflux temperature with stirring for 12 hours. The solvent is removed and the crystalline residue is treated with water. The N-butyl-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[4,3-e]pyrimidin-5-amine is filtered off and recrystallized from ethyl acetate, yield 5 g (77%); m.p. 160°-162°.
Reaction SMILES: [CH2:1]([C@H:8]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[CH2:1]([C@H:8]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)n1c(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C)n1[C@@H](Cc1ccccc1)C(=O)O

Procedure:
L-phenylalanyl methyl ester hydrochloride was converted into the corresponding free base by shaking with a sodium bicarbonate solution in ether and heated to 100° for 2.5 hours in glacial acetic acid with acetonylacetone. Thereafter, the solvent was evaporated and the residue was filtered with toluene over silica gel, to obtain methyl (S)-α-benzyl-2,5-dimethylpyrrole-1-acetate, MS: 258 (M+H)+. The ester so obtained was allowed to stand at room temperature for 1.5 hours with 1N sodium hydroxide solution in a 9:1 mixture of methanol and water. After extracting the aqueous solution with ether and washing the organic phase, there was obtained (S)-α-benzyl-2,5-dimethylpyrrole-1-acetic acid, MS: 244 (M+H)+, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([O:28]CC)=O)=[O:7])=[CH:4][CH:3]=1.[NH3:33].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([NH2:33])=[O:28])=[O:7])=[CH:31][CH:32]=1
Reactant: N
Reactant: CCOC(=O)c1nc(N(C)c2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1ccc2ncccc2c1)c1nc(C(N)=O)c(NC(=O)c2ccc(F)cc2)s1
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of ethyl 5-(4-fluorobenzamido)-2-[methyl(quinolin-6-yl)-amino]thiazole-4-carboxylate (0.14 g, 0.31 mmol) in THF (5 mL) was added 7N NH3-MeOH (5mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were purified by silica gel chromatography eluted with EtOAc to give 110 mg (84% yield) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH:9]([Br:12])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCC(=O)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(Br)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 3′-chloropropiophenone (50.0 g, 297 mmol) in acetonitrile (595 mL) was added bromine (16.67 mL, 327 mmol) at room temperature. The reddish-yellow solution was allowed to stir for 18 h at room temperature. The solution was concentrated in vacuo to provide a reddish solid. The crude material was dissolved in 400 mL of ethyl acetate and washed with 400 mL of water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 72.6 g (98%) of crude product. 1H NMR (CDCl3) δ1.90 (d, J=6 Hz, 3H), 5.21 (q, J=6 Hz, 1H), 7.37-7.88 (m, 3H), 7.98 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[F:33][C:32]1[CH:31]=[CH:30][C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[CH:28][C:27]=1[CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:16])[CH2:26][CH2:25]1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 131 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.43 (dd, 1H, J=6.9, 2.5 Hz), 7.36–7.31 (m, 2H), 7.23–7.17 (m, 1H), 6.93 (t, 2H, J=8.4 Hz), 6.87 (t, 1H, J=8.9 Hz), 6.73–6.68 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.73–2.65 (m, 1H), 2.45 (septet, 1H, J=6.7 Hz), 2.30–2.21 (m, 4H), 1.9–1.77 (m, 5H), 1.70–1.63 (m, 3H), 1.56–1.45 (m, 8H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 526.3 (M+H)+.