Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[C:32]([F:54])=[CH:31][N:30]=1>O1CCCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[C:32]([F:54])=[CH:31][N:30]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ncc(F)c2c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.031 g, 0.123 mmol) in tetrahydrofuran (0.450 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.129 ml, 0.129 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 1-chloro-4-fluoroisoquinoline-6-sulfonate (0.050 g, 0.117 mmol) in THF (0.25 mL) was added drop wise, and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on a 12-g column with 0 to 100% EtOAc/Heptane to afford 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE PPP) as an oily solid. (ESI) 516.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](CCN(C)C)=[CH:5][NH:6]2.[OH-].[Na+].[C:18](O)(=O)C.[N+:22]([CH:25]([CH3:27])[CH3:26])([O-:24])=[O:23]>C(OCC)(=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:26][C:25]([CH3:18])([N+:22]([O-:24])=[O:23])[CH3:27])=[CH:5][NH:6]2
Reactant: CC(=O)O
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)CCc1c[nH]c2cccc(F)c12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(Cc1c[nH]c2cccc(F)c12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A slurry of 4-fluoro-3-(dimethylaminoethyl)-1H-indole (4.3 g, 22.4 mmol) in 14.1 ml of 2-nitropropane is treated with solid NaOH (941 mg, 23.5 mmol), and the resulting mixture is heated at reflux overnight. After cooling to ambient temperature, the reaction mixture is acidified with 10%. aqueous acetic acid (25 ml) and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate (50 ml) and brine (50 ml). The layers are separated, and the organic layer is washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give 3.71 g of 4-fluoro-3-(2-methyl-2-nitropropyl)-1H-indole (76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cn1cccc1CCNS(=O)(=O)c1ccc(F)cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-fluorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:46])[NH:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9](=[O:46])[NH:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:18][NH:19][C:13]=2[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)NCc3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1n[nH]c2cc(NC(=O)NCc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A solution of ethyl 3-(6-(3-benzylureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)propanoate (38.7 mg, 0.063 mmol) in TFA (1 ml) was charged with triethylsilane (12 μl, 0.075 mmol) and stirred at RT for 2 hr. LCMS shows conversion to the desired mass. Purified via mass-triggered reverse-phase HPLC to provide ethyl 3-(6-(3-benzylureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)propanoate (8.4 mg, 0.017 mmol, 27.5% yield) as a white solid (TFA salt). MS ESI calc'd for C19H21N5O3 [M+H]+=368, found 368. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (br s, 1H), 8.85 (s, 1H), 7.85 (s, 1H), 7.51 (s, 1H), 7.32 (m, 4H), 7.25 (m, 1H), 4.36 (d, J=5.9 Hz, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.17 (t, J=7.3 Hz, 2H), 2.79 (t, J=7.3 Hz, 2H), 1.13 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:28][CH:29]([F:31])[F:30])=[CH:15][CH:14]=2)=O)=CC=1)([O-])=O.[NH2:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][C:34]=1[C:39]#[N:40]>>[C:39]([C:34]1[CH:35]=[N:36][N:37]([CH3:38])[C:33]=1[NH:32][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:18][C:17]=2[C:16]([O:28][CH:29]([F:31])[F:30])=[CH:15][CH:14]=1)=[O:10])#[N:40]
Reactant: Cn1ncc(C#N)c1N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2nc(N3CCOCC3)oc12
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2nc(N3CCOCC3)oc12
Yield: 29.1 %

Procedure:
Starting from 4-difluoromethoxy-2-(morpholin-4-yl)-benzooxazole-7-carboxylic acid 4-nitrophenyl ester (100 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (56 mg). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane followed by preparative thin layer chromatography eluting with 3% methanol in dichloromethane afforded the title compound as a white solid (28 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1.CCOC(C)=O>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[S:6][C:5]([NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[N:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:29])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of ethyl 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (170 mg, 0.54 mmol) in pyridine (3 mL) was added 4-fluorobenzoyl chloride (0.09 mL, 0.81 mmol) at 0° C. The mixture was allowed to warm to rt, and stirred overnight. The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with EtOAc, and the resulting solids were collected by filtration to give 140 mg (59% Yield) of the titled compound.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: CCC=CCCCCCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCCCCCC=CCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pentadeca-12-ene-1-ol (22.6 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled pentadeca-12-ene-1-ol with vigorous stirring in about 2 hours. Triethylamine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCI) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield pentadeca-12-ene-1-yl methacrylate in good yields. Pentadeca-12-ene-1-yl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8](=[CH2:12])[CH2:9][CH2:10][OH:11].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:13][C:14]1[CH:19]=[C:18]([C:8](=[CH2:12])[CH2:9][CH2:10][OH:11])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: C=C(Br)CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=C(CCO)c1cccc(Cl)c1

Procedure:
A solution of DME (20 mL) and 2M Na2CO3 (15 mL) containing 3-bromobut-3-en-1-ol (1.40 g, 7.66 mol), (3-chlorophenyl)boronic acid (2.3 g, 14.7 mmol) and Pd(PPh3)4 (0.4 g, 0.35 mmol) was refluxed under an argon atmosphere for 3 hours. The solution was concentrated (to remove excess DME) and partitioned between water and ethyl acetate. The organic phase was washed with 1N NaOH, water (2×) and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.42 (s, 1H); 7.31-7.29 (m, 3H); 5.43 (s, 1H); 5.21 (s, 1H); 3.73 (t, J=6.5 Hz, 2H); 2.77 (t, J=6.3 Hz, 2H); 1.91 (s, 1H). LCMS1 2.95 min. (M-OH)=165.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH3:24]>O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][N:24]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH:19]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-c1ccccc1CBr
Reactant: N
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1ccccc1-2
Reaction time: 48 h

Procedure:
The solution of 2.8 g of 2-(o-bromomethylphenyl)-5-chlorobenzophenone in 20 ml of tetrahydrofuran is added dropwise to the solution of 130 ml of saturated ethanolic ammonia while stirring. After 2 days' standing at room temperature the mixture is evaporated, the residue taken up in methylene chloride, the solution washed with aqueous sodium carbonate, dried, evaporated and the residue crystallized from methanol to give the 9-chloro-7-phenyl-5H-dibenz[c,e]azepine melting at 118°-119°.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:41][CH2:42][CH3:43])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:45]1[C:49]([C:50]2[CH:51]=[C:52]3[C:62](=[CH:63][CH:64]=2)[O:61][C:55]2([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][C:53]3=[O:65])=[N:48][N:47]=[N:46]1>O.CN(C=O)C.CCN(CC)CC>[CH2:42]([O:41][C:33]1[CH:32]=[C:28]([C:29]([N:58]2[CH2:59][CH2:60][C:55]3([CH2:54][C:53](=[O:65])[C:52]4[C:62](=[CH:63][CH:64]=[C:50]([C:49]5[NH:48][N:47]=[N:46][N:45]=5)[CH:51]=4)[O:61]3)[CH2:56][CH2:57]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[CH3:43]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (38 μL), HOBT (41 mg) and WSC hydrochloride (52 mg) were added to a DMF (3 ml) solution of 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (65 mg), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (87 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, then fully washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=4.0 Hz), 8.23 (11, dd, J=8.0, 4.0 Hz), 8.04 (1H, s), 7.92 (1H, s), 7.32 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.86 (3H, s), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=558.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:7][C:2]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To cooled (0° C) concentrated H2SO4 (18.5 mL), was added 3-methyl-3- phenylbutanoic acid (10 g, 56 mmol). Next, a cooled solution of HNO3 (3 mL) in H2SO4 (6.2 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 30 min more. The mixture was poured into ice and the resulting solution was allowed to stand in the refrigerator overnight. The precipitate was filtered, washed with H2 0 and dried, to afford a crude product (14.5 g). This was purified by chromatography on silica gel (CHCl3 :MeOH, 3%) to give the title compound (5.9 g, 47%). 1H NMR (80MHz, CDCl3) δ (TMS): 8.16 (d, J=6.5 Hz, 2H), 7.55 (d, J=6.5 Hz, 2H), 3.5 (m, 1H), 2.70 (s, 2H), 1.50 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH2:18][O:19][CH2:20][C:21]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:17]=2)[N:14]([CH:40]2[CH2:42][CH2:41]2)[N:13]=[CH:12]3)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:40]1([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:17][C:16]=3[CH2:18][O:19][CH2:20][C:21]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:12]=[N:13]2)[CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc3cnn(C4CC4)c23)(c2ccccc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc3cnn(C4CC4)c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-1-cyclopropyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (23 mg, 0.04 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (12.8 mg, 0.2 mmol) and formalin (152 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 23 mg (95%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.71-7.73 (m, 2H), 7.65-7.67 (m, 2H), 7.40 (m, 1H), 7.24-7.30 (m, 4H), 7.16-7.19 (m, 1H), 4.93 (s, 2H), 3.49-3.52 (m, 1H), 3.46 (s, 2H), 2.51-253 (m, 2H), 2.16 (s, 3H), 2.12-2.22 (m, 4H), 1.91-1.96 (m, 2H), 1.21-1.24 (m, 2H), 0.88-0.92 (m, 2H), 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.7 (d, J=246.6 Hz), 145.8 139.1, 133.0, 132.7, 131.9, 128.3, 127.8, 127.3, 127.1, 126.5, 126.1, 122.3, 119.6, 119.1, 110.6, 70.9, 52.0, 50.8, 46.3, 40.8, 32.7, 32.1, 8.2. Mass spec.: 477.41 (MH)+.
Reaction SMILES: O.[C:2]1([CH3:13])[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])=[CH:4][CH:3]=1>[Pt].CCCCCCC>[CH3:13][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=2[CH:3]=1
Reactant: CC=CCCc1ccc(C)cc1
Agent: [Pt]
Solvent: O
Solvent: CCCCCCC
Product: Cc1ccc2cccc(C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Deionized water (500 parts) was added to H mordenite (15 parts) made by Tosoh Corporation, silica (270 parts), and alumina sol (21 parts) containing 70 weight percent alumina as a binder, and the mixture was thoroughly stirred at room temperature. After shaping of the slurry with an extruder, the shaped article was dried at 110° C. and then calcined at 350° C. for 3 hours to prepare a catalyst. After this catalyst was packed into a cylindrical stainless-steel cyclization reactor, 5-(p-tolyl)-2-pentene prepared by the preceding step was fed at a rate of 10 parts/hr while nitrogen was fed at a rate of 250 parts/min to complete a cyclization reaction at a temperature of 170° C. under normal pressure. The molar ratio of the diluent solvent to the raw material was 11. After the cyclization reaction, the reaction solution was fed to a cylindrical stainless-steel dehydrogenation reactor filled with 40 parts of 1%-platinum/activated charcoal catalyst (made by N.E. CHEMCAT). The reaction temperature was 280° C. During the dehydrogenation reaction, n-heptane as the diluent solvent was also fed at a rate of 20 parts/hr. After the reaction, the solution was fed to a glass distillation column under a reduced pressure of 19 kPa to recover n-heptane. The residual reaction solution after the removal of n-heptane was fed to a glass distillation column under a reduced pressure of 13 kPa to separate low-boiling-point components at a rate of 0.05 parts/hr and high-boiling-point components at a rate of 0.3 parts/hr and to isolate 9.4 parts of 1,7-DMN with a purity of 98% from a middle plate of the distillation column.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22][CH:23]=1)[N:14]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[N:13]=[CH:12]2)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[N:22][CH:23]=1)[N:14]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[N:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2O)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.9 %

Procedure:
To a solution of tert-butyl 5-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-ylcarbamate (260 mg, 519 μmol) in EtOH (25 mL) and EtOAc (25 mL) is added Pd/C (100 mg, 10% wt) under N2. The resulting mixture is degassed by evacuation and backfilled with nitrogen. Then the reaction mixture is stirred at RT under H2 atmosphere for 6 hours. The reaction mixture is filtered. The filtrate is concentrated to give the product (200 mg, 93.8% yield). MS (m/z): 411.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:16][C@@H:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[CH2:18][OH:19].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:16][C@@H:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=3)[CH2:18][OH:19])=[O:13])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(C2CC2)cc1)N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-2-methylpropane-2-sulfinamide (3.84 g, 11.3 mmol) and methanol (50 ml) was added 2.0N HCl in ether (45.1 ml, 90 mmol). The reaction was stirred for an hour and concentrated to give (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride as a white foam (3.49 g, 100%). MS (Electrospray): m/z 237.1 (M+H). To a 100 ml round bottom flask equipped with a magnetic stir bar were added 4-cyclopropylphenylacetic acid (1.79 g, 10.2 mmol), (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride (3.14 g, 10.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.34 g, 12.2 mmol), 1-hydroxy-7-azabenzotriazole (1.66 g, 12.2 mmol) and triethylamine (4.25 ml, 30.5 mmol) into 68 ml of dimethylformamide. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was washed with brine (3×50 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give an oil. Purification by flash chromatography (SiO2, 50-100% EtOAc/Hexanes, gradient) gave 2-(4-cyclopropylphenyl)-N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a light yellow solid (3.00 g, 75%); 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=2.4 Hz, 1H), 7.42 (dd, J=2.4 Hz and 6.8 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 2H), 7.01 (d, J=6.4 Hz, 2H), 5.07-4.99 (m, 1H), 4.63 (q, J=6.4 Hz, 2H), 3.82-3.79 (m, 2H), 3.54 (s, 2H), 1.89-1.84 (m, 1H), 0.92 (m, 2H), 0.64 (m, 2H); MS (Electrospray): m/z 395.2 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18]Br>C(COC)OC.CCOCC>[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18][CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Cc1ccccc1
Reactant: Clc1ccccc1C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1ccccc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (6.30 g., 0.15 mole, oil dispersion) is suspended in glyme (200 ml.) and phenyl acetone (20.13 g., 0.15 mole) is added dropwise with stirring. After complete addition, the mixture is heated to reflux for one hour. The mixture is cooled to room temperature, and a solution of crude o-chlorocinnamyl bromide (39.05 g., 0.17 mole) in glyme (100 ml.) is added dropwise with stirring. When addition is complete, the mixture is heated on a steam bath for 24 hours then allowed to cool. Filtration and removal of solvent in vacuo produces a yellow oil. This oil is taken up in ether (400 ml.), washed with a very dilute hydrochloric acid solution, followed by a washing with brine, and is finally dried over Na2SO4. Filtration and removal of solvent in vacuo yields the crude product as a dark oil. Vacuum distillation provides 24.9 g., b.p. 153°-155°/0.1 mm.