Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(-n2cncn2)c(F)c1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: O=C(c1ccc(-n2cncn2)c(F)c1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.00 min; Mass spectrum (ESI+): m/z=442 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[N:13][CH:14]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(F)cn2)CC1
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc(F)cn2)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(5-fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.92 g, 3.6 mmol) and hydrazine hydrate (0.80 ml, 16 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.55 g, 67%) as white solid, which was used in the next step without further purification. MS m/e: 254 (M+H+)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[C:4]1([C:1](=[O:3])[CH2:2][C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)C(=O)OC
Product: COC(=O)C(=O)CC(=O)c1ccccc1

Procedure:
Methyl 4-phenyl-2,4-dioxobutanoate (10 g) obtained by acetophenone and dimethyl oxalate as starting materials and methylhydrazine were reacted in ethanol (60 ml) at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (mobile phase:dichloromethane) to give methyl 1-methyl-3-phenylpyrazole-5-carboxylate (3.0 g) and methyl 1-methyl-5-phenylpyrazole-3-carboxylate (3.6 g).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[O:3][C:4]1[CH:42]=[CH:41][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][NH:23][C:22](=[O:26])[C:21]=4[N:27]=3)[CH2:15][CH2:14][N:13]2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:11])=[CH:6][CH:5]=1.CO.[C:47]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:44][C:2]([F:1])([F:43])[O:3][C:4]1[CH:42]=[CH:41][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][N:23]([CH3:47])[C:22](=[O:26])[C:21]=4[N:27]=3)[CH2:15][CH2:14][N:13]2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:11])=[CH:6][CH:5]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3c(=O)[nH]ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc2sc(N3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)[C@@H](C(=O)NCc4ccc(OC(F)(F)F)cc4)C3)nc2c1=O
Yield: 71 %

Procedure:
To a solution of the compound (40 mg) obtained in Step 6 in THF (0.8 ml) were added methanol (3.7 μl), triphenylphosphine (24 mg) and diisopropyl azodicarboxylate (18 μl) with stirring under ice-cooling, and the mixture was stirred overnight at room temperature. Methanol (1.2 μl), triphenylphosphine (8 mg) and diisopropyl azodicarboxylate (6 μl) was added at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=5:95) to give the title compound (29 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:27]4[CH2:28][CH2:29][CH:24]([O:23][CH2:21][CH3:22])[CH2:25][CH2:26]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCOC1CCNCC1
Product: CCOC1CCN(c2cc3c(c(C)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 40 %

Procedure:
The condensation of 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-ethoxypiperidine in a similar manner as described in example 1 give the titled product. Yield 40%, m.p 180–82° C., C21H21FN2O4, m/z 388 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:31][CH2:30][N:29]([CH3:34])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(C)CC4)nc3-c3ccc(F)cc3F)nn12
Reaction time: 1 h
Yield: 40 %

Procedure:
The 6-(3-(2,4-difluorophenyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.10 g, 0.24 mmol; Example #Q.2.1) was suspended in DCE (5 mL) and then formaldehyde (30% solution in water, 0.12 g, 1.18 mmol) and sodium triacetoxyborohydride (0.10 g, 0.47 mmol) were added. After about 1 h, the mixture was concentrated under reduced pressure, dissolved in DMF/HOAc, and purified by RP-HPLC (Table 1, Method d). The appropriate fractions were combined and concentrated under reduced pressure and then the mixture was basified with 2 N NaOH and extracted with EtOAc. The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. Evaporation several times with Et2O/heptane gave a white solid which was collected by filtration and dried under vacuum to give the title compound (0.042 g, 41%): LC/MS (Table 1, Method a) Rt=1.83 min; MS m/z: 438.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cc(F)cc(F)c4)c32)[nH]1

Procedure:
4-(3,5-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 40 mg of the titled compound as a yellow solid.
Reaction SMILES: [Mg].C1C[O:5][CH2:4]C1.Br[C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CN(C=O)C>[CH2:23]([CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:4]=[O:5])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCC(CCCCCC)Cc1ccsc1Br
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Solvent: CN(C)C=O
Product: CCCCCCCCC(CCCCCC)Cc1ccsc1C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Magnesium (345 mg, 14.2 mmol) was added to a flask and put under a nitrogen atmosphere after sufficient deaeration. THF (10 ml) was added, and 2-bromo-3-(2-hexyldecyl)thiophene (A2) (5 g, 12.9 mmol) was dropped while refluxing THF. After the dropping, refluxing was similarly performed for three hours. THF (40 ml) was then added, and the flask was cooled to 0° C. DMF (10 ml) was dropped, and the temperature was increased to room temperature. The mixture was then stirred overnight. To the reaction solution, 1N hydrochloric acid (20 ml) was added, followed by extraction with chloroform. An organic layer was then washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and chloroform was used as a mobile phase, 3-(2-hexyldecyl)-2thiophenaldehyde (A3) was obtained as clear oil (3.0 g, 69% yield). The product (A3) obtained was identified using a 1H-NMR method. 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.03 (s, 1 H), 7.64 (d, J=4.9 Hz, 1 H), 6.97 (d, J=4.9 Hz, 1 H), 2.88 (d, J=7.3 Hz, 2 H), 1.25 (m, 25 H), 0.88 (m, 6 H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[C:35]([Cl:37])[C:9]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[O:11])=[C:8]([Cl:38])[CH:7]=1.O=C1CCC(=O)N1[O:46][C:47](=O)[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][NH:86][C:87](=[O:97])[CH2:88][CH2:89][N:90]1[C:94](=[O:95])[CH:93]=[CH:92][C:91]1=[O:96].CCN(C(C)C)C(C)C>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C:9]2[C:8]([Cl:38])=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47](=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][NH:86][C:87](=[O:97])[CH2:88][CH2:89][N:90]3[C:94](=[O:95])[CH:93]=[CH:92][C:91]3=[O:96])=[CH:36][C:35]=2[Cl:37])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=1)=[O:34]
Reactant: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (143 mg, 0.2 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro- pyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (173 mg, 0.2 mmol), and DIPEA (258 mg, 348 uL, 2.0 mmol), and after HPLC purification, resulted in a white solid (45 mg, 16.6%). ES(+)-HRMS m/e calcd. for C60H81Cl4N5O21 (M+Na)+ 1370.4070, obsd. 1370.4066.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C1C(=O)N([Cl:22])C(=O)C1.CO>CN(C=O)C>[Cl:22][C:5]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Temperature: 20 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione) (10.52 g, 54.7 mmol) in anhydrous DMF (60 ml) was added NCS (8.04 g, 60.2 mmol). The reaction mixture was left to stir under nitrogen at 20° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an amber oil. MeOH was added and left to stand for 18 hours. The resulting residue was filtered and dried under vacuum to give the title compound (7.69 g, 62%). m/z 227.2[MH+].
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45]OS(C)(=O)=O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:51][CH2:52][CH2:53][OH:54].[I-].[Na+]>C(#N)C.C(O)C>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][CH2:45][NH:51][CH2:52][CH2:53][OH:54])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCCOS(C)(=O)=O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCO
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: OCCNCCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(3-hydroxypropoxy)phenyl]ethyl)benzofuran (0.23 g) and triethylamine (0.1 mL) in dichloromethane (6 mL) was added methanesulfonyl chloride (0.042 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-{(4-[3-(methanesulfonyloxy)propoxy]phenyl}ethyl)benzofuran (0.25 g). The obtained 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-{4-[3-(methanesulfonyloxy)propoxy]phenyl}ethyl)benzofuran (30 mg) was dissolved in acetonitrile (0.5 mL)-ethanol (0.5 mL). To the solution were added 2-aminoethanol (0.025 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (15 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)CCc2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), ethyl piperidine-4-carboxylate (16.77 mg, 0.107 mmol), and TEA (0.025 mL, 0.178 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (2 mL) and purified by HPLC to give the title compound. LCMS m/z=477.5 [M+H]+; 1.19 (t, J=7.1 Hz, 3H), 1.25 (d, J=6.8 Hz, 0.3H), 1.37-1.50 (m, 2H), 1.44 (d, J=6.7 Hz, 2.7H), 1.67-1.77 (m, 1H), 1.77-1.89 (m, 2H), 1.99-2.09 (m, 2H), 2.20-2.31 (m, 1H), 2.45-2.56 (m, 1H), 2.57-2.79 (m, 3H), 2.92 (t, J=6.6 Hz, 2H), 3.00-3.19 (m, 5H), 3.34-3.47 (m, 1H), 3.50-3.59 (m, 1H), 3.70-3.86 (m, 2H), 4.06 (q, J=7.0 Hz, 2H), 3.70-3.86 (m, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([OH:24])([CH3:22])[CH3:23])[N:20]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)(O)c1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)O)n1
Temperature: 130 °C
Yield: 59 %

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (0.45 g, 2.04 mmol) and 2-(6-aminopyridin-2-yl)propan-2-ol (620 mg, 4.07 mmol) was dissolved in acetonitrile (3.00 mL) and heated at 130° C. for 18 h. The mixture was cooled, concentrated, the residue was adsorbed on silica gel and purified by flash chromatography (silica gel 45 μM, 160 g, Thomson) eluting with 0 to 100% hexanes/ethyl acetate over 40 min, to yield ethyl 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (405 mg, 59.1% yield). 1H NMR (CHLOROFORM-d) δ: 10.72 (s, 1H), 9.00 (s, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 5.21 (br. s., 1H), 4.60 (q, J=7.2 Hz, 2H), 1.67 (s, 6H), 1.54 (t, J=7.9 Hz, 3H); LC-MS 337.0, 339.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:14][C:8]=2[C:7]=1[OH:19])=[O:5])[CH3:2].[Br:20]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:20])[C:9]2[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:14][C:8]=2[C:7]=1[OH:19])=[O:5])[CH3:2]
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCOC(=O)c1ncc2nc(C(C)(C)C)sc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Yield: 68.6 %

Procedure:
A solution of 2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (3.87 g, 13.8 mmol, example 166(d)), N-bromosuccinamide (2.67 g, 15 mmol), and benzoyl peroxide (315 mg, 1.3 mmol) in 46 mL of carbon tetrachloride was heated at reflux temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography, eluting the desired product from silica gel with a gradient of 0-30% ethyl acetate in hexanes to give 3.4 g of the title compound. MS (ESI−): 356.99, 358.98 e/z (M−1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:23][CH3:24])[N:19]=[C:20]([CH3:22])[CH:21]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:23][CH3:24])[N:19]=[C:20]([CH3:22])[CH:21]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCn1nc(C)cc1C1CCN(CCC(=O)c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C1CCN(CCC(O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A solution of the product of Step 1 (90 mg, 0.25 mmol), in EtOH (10 mL) was treated with NaBH4 (38 mg, 1.0 mmol) and stirred at RT for 1 h. The reaction was quenched with NH4Cl solution, then the EtOH was removed under reduced pressure. The residue was partitioned between CH2Cl2 and water and the organic layer separated and the aqueous re-extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 1-(4-chloro-phenyl)-3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-ol as a gum (30 mg). This intermediate was dissolved in THF (5 mL), treated with N-methylbenzenesulfonamide (17 mg, 0.1 mmol), PPh3 (26 mg, 0.1 mmol) and DIAD (20 μL, 0.1 mmol) and stirred overnight at RT. The solvent was evaporated under reduced pressure and the residue dissolved in CH2Cl2 and loaded onto a 5 g SCX cartridge, which was eluted with CH2Cl2 then 2M NH3 in MeOH solution. The fractions containing the desired material were concentrated under reduced pressure and were further purified by silica chromatography eluting 1–3% MeOH/CH2Cl2 to yield the desired sulfonamide. 1H NMR (CDCl3, 400 MHz) δ 7.70 (2H, d, J=7.3 Hz), 7.48 (1H, d, J=7.3 Hz), 7.40 (2H, t, J=7.3 Hz), 7.20–7.15 (2H, m), 7.07 (2H, d, J=8.4 Hz), 5.73 (1H, s), 5.07 (1H, t, J=7.3 Hz), 3.94 (2H, q, J=7.4 Hz), 2.92–2.68 (2H, m), 2.60 (3H, s), 2.48–2.32 (1H, m), 2.28–2.05 (5H, m), 2.05–1.40 (8H, m), 1.33 (3H, t, J=7.4 Hz). MS (ES+) C27H35ClN4O2S requires: 515, found: 515/517 (3:1, M+H+)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Yield: 67.2 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.24 g, 5.06 mmol) and phenyl chloroformate (1.90 mL, 15.0 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (1.24 g, 3.40 mmol, 67%). 1H NMR (300 MHz, DMSO-d6) δ 9.96 (br s, 1H), 7.44-7.06 (m, 9H), 6.31 (s, 1H), 3.81 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 366 (M+H)+.