Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCCO
Reactant: COc1ccccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Product: COc1ccccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 442 (0.27 mmol) and but-3-yn-1-ol (0.30 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 20:80 as the eluent to afford the title compound. 13C NMR (DMSO-d6) δ 193.6, 152.4, 150.2, 145.6, 141.1, 135.9, 134.4, 134.2, 134.0, 132.3, 128.2, 125.3, 124.6, 123.4, 121.0, 120.6, 118.8, 115.1, 112.2, 111.7, 60.1, 55.4, 29.1, 19.0
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14](=[O:21])OCC(Cl)(Cl)Cl)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:22]1([C:28]2[N:29]=[C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([N:36]3[CH2:37][CH2:38][N:33]([C:30]4[S:31][CH:32]=[C:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:29]=4)[CH2:34][CH2:35]3)=[O:21])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N1CCc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1CCc2cc(NC(=O)N3CCN(c4nc(-c5ccccc5)cs4)CC3)ccc21

Procedure:
A solution of 2,2,2-trichloroethyl (1-acetyl-2,3-dihydro-1H-indol-5-yl)carbamate (200 mg, 0.569 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (140 mg, 0.569 mmol), diisopropylethylamine (0.198 ml, 1.14 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 48 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (92.0 mg, 36.1%) as a solid.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH3:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=[O:10].Cl>CCOCC>[F:7][C:8]([F:13])([F:12])[C:9](=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 51.2 %

Procedure:
In a nitrogen atmosphere, 9.12 g (380 mM) of magnesium into 120 ml of ether, and 49.32 g (360 mM) of butyl bromide dissolved in 30 ml of ether was added thereto, followed by 1.5 hours of heat refluxing. After cooling by standing and with ice, 13.68 g (120 mM) of trifluoroacetic acid dissolved in 30 ml of ether was added. After being stirred for 7 hours under cooling with ice, the system was subjected to hydrolysis with addition of hydrochloric acid, followed by extraction with ether and drying of the resultant ether layer with anhydrous sodium sulfate. The dried product was distilled under normal pressure to obtain 9.46 g of 1,1,1-trifluoro-2-hexanone. Yield: 47%.
Reaction SMILES: C([N:3](CC)CC)C.[NH2:8][C:9]1[C:14]2[CH2:15][CH2:16][O:17][C:13]=2[C:12]([C:18](O)=[O:19])=[CH:11][C:10]=1[Cl:21].ClC(OCC)=O.N>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]2[CH2:15][CH2:16][O:17][C:13]=2[C:12]([C:18]([NH2:3])=[O:19])=[CH:11][C:10]=1[Cl:21]
Reactant: CCN(CC)CC
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(Cl)c(N)c2c1OCC2
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
Triethylamine (0.16 mol) was added to a solution of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.16 mol) in chloroform (600 ml) at a temperature below 10° C. Ethyl chloroformate (15.3 ml) was added afterwards and the reaction mixture was stirred for 45 minutes, while cooling on an ice-bath. Gaseous ammonia was allowed to bubble through the mixture and the reaction mixture was stirred for 3 hours at RT. The precipitate was filtered off and consecutively washed with water, 5% NaOH solution, and again water, and dried, yielding 23.5 g (69%) of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxamide (intermediate 7).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](Cl)=[O:10])[CH:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:10])[CH:3]=1
Reactant: Cc1nc(Cl)cc(C(=O)Cl)n1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Temperature: 0 °C

Procedure:
2.48 g (13.0 mmol) 6-chloro-2-methyl-pyrimidine-4-carboxylic acid chloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and 6.93 g (52.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. The mixture was combined with ice water and the precipitate formed was suction filtered and washed with water. Then the precipitate was dissolved in MeOH/DCM and filtered through silica gel suction. The filtrate was evaporated down and the residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and triturated with diethyl ether. The precipitate was suction filtered, washed with diethyl ether and dried i. vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: COCCN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cc2C#N)CC1
Product: COCCNC1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 51.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 151 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and 5-amino-2-[4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl) amino]piperidin-1-yl]benzonitrile (0.9 g), the title compound (0.6 g) was obtained, melting point: 194° C.
Reaction SMILES: C(NCC)C.[CH3:6][O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)[N:13](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH:12]([CH:42]=[CH:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:11]1)=[O:9]>C(#N)C>[CH2:47]([O:46][C:44]([CH:43]=[CH:42][CH:12]1[NH:13][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)[CH2:15][N:10]([C:8]([O:7][CH3:6])=[O:9])[CH2:11]1)=[O:45])[CH3:48]
Reactant: CCOC(=O)C=CC1CN(C(=O)OC)CC(c2cc(F)c(F)c(F)c2)N1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CC#N
Product: CCOC(=O)C=CC1CN(C(=O)OC)CC(c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethylamine (2 mL) was added to a solution of 2-(2-ethoxycarbonylvinyl)-6-(3,4,5-trifluorophenyl)piperazine-1,4-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester 4-methyl ester (1.03 g) in acetonitrile (10 mL), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (heptane->ethyl acetate) to obtain 422 mg of an E/Z isomer mixture of the title compound. The property value of the compound is as follows.
Reaction SMILES: O[CH2:2][C:3]12[CH2:8][CH:7]1[CH2:6][CH2:5][CH2:4]2.[CH2:9]([NH2:11])C>>[C:3]12([CH2:2][CH2:9][NH2:11])[CH2:8][CH:7]1[CH2:6][CH2:5][CH2:4]2
Reactant: OCC12CCCC1C2
Reactant: CCN
Product: NCCC12CCCC1C2

Procedure:
In this preparation 1-(hydroxymethyl)-bicyclo[3.1.0]hexane is treated in the same manner as described in paragraphs b.-d. of Preparation A affording 2-bicyclo[3.1.0]hex-1-yl)ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8](B(O)O)=[CH:9][C:5]=2[CH:4]=1.Br[C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:28][CH:29]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(B(O)O)cc2c1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Product: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield by essentially following the procedures in Example 1, Part B, from 5-methoxybenzo[b]thiophene-2-boronic acid (Part B) and 1-(2-(4-bromophenoxy)ethyl)pyrrolidine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[N:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:19][CH:18]=1
Reactant: Clc1cc(N2CCN(Cc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: c1cc(N2CCNCC2)ncn1
Reaction time: 8 h
Yield: 76 %

Procedure:
1-(Benzyl)-4-(4-chloropyrimidin-6-yl)piperazine (58.0 g) was dissolved, with some heating, in methanol (700 ml), treated with 10% Pd on activated carbon (11.6 g) and agitated and hydrogenated at atmospheric pressure for 8 h. The catalyst was removed by filtering through celite. The filtrate thus obtained was then evaporated under reduced pressure to a yellow-brown viscous gum which was chromatographed through 60 υm silica gel, eluting with 5% methanol, 1% ammonium hydroxide and 94% dichloromethane to obtain 4-(4-pyrimidinyl)piperazine, as a white solid, 25 g (76% yield based on prehydrogenation substrate);
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:23]2[CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:32]=3[CH3:41])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[O:9][C:8]1=[O:42].O.[OH-].[Li+].O.Cl>C(OCC)(=O)C.O1CCOCC1>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=2[C:23]2[CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=3[CH3:41])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[O:9][C:8]1=[O:42]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (21 mg, 0.029 mmol), lithium hydroxide monohydrate (9 mg, 0.21 mmol), water (0.4 mL) and 1,4-dioxane (1 mL) were stirred at 20° C. for 2 hours to complete the hydrolysis. The reaction mixture was acidified by HCl (aq., 1 mL). The resulting crude mixture was worked up with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to a clear oil. This oil was purified by a preparative reverse-phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluted with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled and evaporated to afford 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=711.17; found=712.28 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) δ 8.01 (s, 0.4H), 7.97 (s, 0.6H), 7.95 (d, J=7.0 Hz, 0.4H), 7.93 (d, J=6.5 Hz, 0.6H), 7.81 (s, 0.4H), 7.77 (s, 0.6H), 7.75 (s, 0.4H), 7.71 (s, 0.6H), 7.68 (d, J=6.5 Hz, 0.6H), 7.66 (d, J=6.5 Hz, 0.4H), 7.62 (s, 1H), 7.55 (s, 1H), 7.41-7.35 (m, 2H), 7.32 (d, J=6.5 Hz, 0.4H), 7.23 (d, J=6.5 Hz, 0.6H), 7.16 (d, J=2 Hz, 0.4H), 7.08 (d, J=7.5 Hz, 0.6H), 7.02 (d, J=7.5 Hz, 0.4H), 6.98 (d, J=2.0 Hz, 0.6H), 5.22 (d, J=4 Hz, 0.6H), 5.13 (d, J=4.5 Hz, 0.4H), 4.82, 4.75 (d, J=13.5 Hz, 1H), 4.29, 4.26 (d, J=15.5 Hz, 1H), 3.86 (s, 1.8H), 3.59 (s, 1.2H), 3.53-3.48 (m, 0.4H), 3.30-3.24 (m, 0.6H), 2.36, 2.22 (s, 3H), 0.89, 0.75 (d, J=5.5 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:66][N:67]1[CH2:72][CH2:71][N:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[C:30]([N:76]3[CH2:75][CH2:74][CH:73]([N:70]4[CH2:69][CH2:68][N:67]([CH3:66])[CH2:72][CH2:71]4)[CH2:78][CH2:77]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1ccc2c(c1)OCCO2)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3ccc4c(c3)OCCO4)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
A solution of 35 mg (0.07 mmol) (R)-1-carboxy-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 25 mg (0.08 mmol) TBTU, 11 μL (0.08 mmol) triethylamine and 14 mg (0.08 mmol) 1-methyl-4-piperidin-4-yl-piperazine in 1 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:15]2[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH2:6][CH2:7]3)[CH:16]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1C1CCN(C(=O)C(F)(F)F)CC1

Procedure:
To a solution of 2,2,2-trifluoro-1-[4-(2-methoxyphenyl)piperidin-1-yl] ethanone (0.285 g; 1 mmol), prepared as in Example 1 Step 1, and 4-chlorobenzenesulfonyl chloride (0.210 g; 1 mmol) in 1,2-dichloroethane (2 mL) at 0° C. under nitrogen atmosphere was added, in small portions, aluminum chloride (0.134 g; 1 mmol), and the mixture was refluxed for 18 h. After cooling to 0° C. a solution of 2N HCl (2 mL) was added and the mixture was extracted into dichloromethane (20 mL). The organic phase was dried (Na2SO4), concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate (7:3, v/v) to give 1-{4-[5-(4-chloro-benzenesulfonyl)2-methoxyphenyl]piperidin-1-yl}2,2,2-trifluoro-ethanone (31) as white solid (0.077 g; 17%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1)[CH2:2][CH3:3].[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21].Cl.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1.O>[O:10]=[C:8]1[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[CH2:9]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCCNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCN(C(=O)c1cccc([N+](=O)[O-])c1)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reaction time: 19 h

Procedure:
4,5-Dihydro-3-propylamino-5-oxo-1-(2,4,6-trichloro-phenyl)-1H-pyrazole (21.9 g, 68.3 mmol) was dissolved in a mixture of tetrahydrofuran (170 ml) and pyridine (34 ml) and the solution was cooled in an ice-bath. m-Nitrobenzoyl chloride (25.35 g, 136.7 mmol) was dissolved in tetrahydrofuran (40 ml) and the solution was added dropwise to the stirred, cooled mixture. Stirring was continued at room temperature for 19 hrs. A further quantity of m-nitrobenzoyl chloride (10%) was added and the mixture was stirred for 2 hrs to complete the reaction. The mixture was poured into dilute hydrochloric acid (31) and the oily solid was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4). The solvent was removed by evaporation and replaced with ethanol (300 ml). A solution of sodium hydroxide (13.7 g, 324 mmol) in water (40 ml) was added dropwise and the mixture was stirred for 1 hr. The mixture was poured into dilute hydrochloric acid (21) and the resulting oil was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4). The solvent was evaporated under reduced pressure to give a resin, 33.0 g, ca 100%. This was used in the next stage without purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@:24]([OH:28])([CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1>CCCCCCC.CCO.CO>[OH:28][C@:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cc[nH]n1
Solvent: CCCCCCC
Solvent: CCO
Solvent: CO
Product: C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 15 using (R)-5-bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 14.1) and (1H-pyrazol-3-yl)boronic acid to afford a white solid. HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent: n-heptane/EtOH/MeOH (80:12:8), 1 mL/min, UV 210 nm) tR=5.49 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=448.3 [M+H]+, m/z=446.1 [M−H]−, 492.1 [M+formic acid-H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.65-1.81 (m, 2H) 2.99 (d, J=10.54 Hz, 1H) 3.06 (d, J=11.80 Hz, 1H) 3.24-3.33 (m, 1H) 3.48 (td, J=10.20, 7.22 Hz, 1H) 4.68 (s, 1H) 6.38 (d, J=2.01 Hz, 1H) 7.33 (d, J=9.16 Hz, 2H) 7.75 (br. s, 1H) 7.83-7.90 (m, 2H) 8.03 (d, J=2.51 Hz, 1H) 8.73 (d, J=2.38 Hz, 1H) 10.19 (br. s, 1H) 12.96 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:45])=[C:7]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([C:31](=[O:41])[NH:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])([CH3:30])[CH3:29])=[CH:16][CH:15]=3)=[C:11]([C:42]#[N:43])[CH:10]=[N:9][N:8]2[CH:44]=1)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:45])=[C:7]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([C:31](=[O:41])[NH:32][CH2:33][C:34]([OH:36])=[O:35])([CH3:30])[CH3:29])=[CH:16][CH:15]=3)=[C:11]([C:42]#[N:43])[CH:10]=[N:9][N:8]2[CH:44]=1)=[O:4]
Reactant: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCC(=O)OC(C)(C)C)cc3)c2c1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCC(=O)O)cc3)c2c1C
Yield: 87.8 %

Procedure:
A solution of ester 388 (292 mg, 0.476 mmol) in TFA/CH2Cl2/H2O (5 ml, 48/48/4) was stirred for 2 h at rt, concentrated and purified by silica gel flash column chromatography to afford the title compound (233 mg, 89%) as a crystalline yellow powder (4%-12% MeOH—CH2Cl2). LCMS Found: (M+H)+=558.0
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](F)C1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f62) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:7])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
0.35 g (0.8 mmol) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid was refluxed together with 0.15 g (0.9 mmol) of N,N'-carbonyldiimidazole in 15 ml of absolute tetrahydrofuran for 2 hours, Then, 1.03 ml (10 mmols) of benzyl alcohol were added, and the mixture was refluxed for 3.5 hours. The reaction mixture was then evaporated in vacuo, and the residue was purified by column chromatography on silica gel (chloroform/acetone=9/1).