Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH2:60])[CH3:59]>>[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH:60][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([I:25])=[CH:27][C:28]=1[NH:35][S:36]([C:39]1[C:40]2[N:41]=[CH:42][CH:43]=[N:44][C:45]=2[CH:46]=[CH:47][CH:48]=1)(=[O:38])=[O:37])[CH3:59]
Reactant: C[C@@H](N)c1ccc(F)cc1F
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1F

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and (R)-1-(2,4-difluorophenyl)ethylamine hydrochloride (EXAMPLE 2, Method 1, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H17F2IN4O3S, 594.0; m/z found, 593 [M−H]−. HPLC (reverse phase): RT=10.16 min. 1H NMR (500 MHz, CDCl3): 11.22 (s, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.55 (dd, J=7.4, 1.4 Hz, 1H), 8.30 (dd, J=7.4, 1.4 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.32-7.27 (m, 2H), 6.99 (d, J=8.2, 1H), 6.89-6.85 (m, 1H), 6.85-6.80 (m, 1H), 6.33 (br d, J=7.7 Hz, 1H), 5.35-5.27 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: C([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[N:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[CH3:22][N:13]1[C:14]2[N:15]=[N:16][N:17]([CH3:21])[C:18]=2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:23])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-3,7-dimethyl-8-azaxanthine (71 mg, 0.22 mmol) in methanol (15 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). The mixture was stirred at room temperature for 24 hours and then the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-3,7-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12464) (55 mg, 88% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:32]I>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[C:13]2[CH2:14][CH:15]([CH2:17][O:18][CH3:32])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(CO)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
NaH (50 mg, 60% in mineral oil, 1.3 mmol) was added to a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200g) (409 mg, 0.97 mmol) in THF (5 mL). The resulting mixture was stirred at 0° C. for 10 min and then methyl iodide (80 uL, 1.3 mmol) was added. The mixture was stirred at room temperature for 2 hr and then quenched with H2O (20 mL), extracted with EtOAc (2×20 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 1.56 (s, 9 H) 2.89 (dd, J=16.55, 7.20 Hz, 1 H) 3.07 (s, 3 H) 3.08-3.17 (m, 1 H) 3.39-3.44 (m, 3 H) 3.58 (d, J=5.05 Hz, 2 H) 4.99-5.08 (m, 1 H) 7.04-7.10 (m, 2 H) 7.21 (d, J=1.01 Hz, 1 H) 7.30 (d, J=1.26 Hz, 1 H) 7.86-7.93 (m, 2 H); LCMS for C22H26O7S m/z 457.00 (M+Na)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[OH:19][C:5]1[CH:4]=[C:3]([CH2:2][C:20]#[N:21])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: [C-]#N
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of benzyl bromide 4 (0.0758 g, 0.238 mmole) in 5 mL dimethylformamide was added pulverized potassium cyanide (0.0232 g, 0.3563 mmole) and 18-crown-6 ether (0.100 g, 0.378 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.046 g (82%) of benzylnitrile 5 as a yellow solid: Mp=128–130° C.; 1H NMR (DMSO-d6) δ 7.85 (d, 2 H, 8.7 Hz), 7.19 (s, 1 H), 7.06 (d, 2 H, J=8.7 Hz), 7.00 (d, 1 H, J=2.5 Hz), 6.88 (d, 1 H, J=2.1 Hz), 3.82 (s, 3 Hz), 3.79 (s, 3 H); MS, 285 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:31][CH3:32])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23](Cl)=[C:22]([Br:30])[CH:21]=2)(=[O:19])=[O:18])[CH:16]=1)=[O:11].C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:31][CH3:32])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:22]([Br:30])[CH:21]=2)(=[O:19])=[O:18])[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Cl)c([N+](=O)[O-])c2)c(SC)s1
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Nc3ccccc3)c([N+](=O)[O-])c2)c(SC)s1
Temperature: 80 °C
Yield: 97 %

Procedure:
A mixture of aniline (112 mg, 1.35 mmol), 4-(3-bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 318: step c) 53 mg, 0.11 mmol), and sodium acetate (16.5 mg, 0.2 mmol) in dioxane (3 mL) was heated at 80° C. for 24 h. The mixture was partitioned between EtOAc (50 mL) and 0.5 N HCl (10 mL) and the organic layer was further extracted with 0.5 N HCl (2×10 mL), NaHCO3 (10 mL), and brine (20 mL). Drying of the solution over sodium sulfate followed by concentration yielded the product (58 mg) which was used without further purification. 1H-NMR (CDCl3): δ 8.04 (s, 1H), 7.64 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=1.9 Hz), 7.25 (m, 2H), 6.95 (m, 1H), 6.69 (m, 2H), 5.70) (s, 1H), 3.90 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH3:2].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCON=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCONCc1ccc(F)cc1
Yield: 74 %

Procedure:
Reduction of 4-fluorobenzaldehyde O-ethyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography (74% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 1.13 (3H, t, J=7.1 Hz, CH3), 3.70 (2H, q, J=7.1 Hz, OCH2), 3.78 (2H, d, J=5.4 Hz, NCH2), 5.20 (2H, broad t, NH), 6.89 (2H, m, aromatics), 7.09 (2H, m, aromatics). Anal. calcd for C9H12FNO: C, 63.88; H, 7.14; N, 8.27. Found: C, 63.68; H, 7.08; N, 8.46.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:28][C@@H:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][N:24]=2)[CH3:27])=[O:10])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc([C@@H](C)N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
To a mixture of 4-biphenylacetic acid (2.00 g, 9.42 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethanamine hydrochloride (1.96 g, 10.36 mmol), 1-hydroxy-7-azabenzotriazole (1.70 g, 12.49 mmol) and diisopropyl-ethyl amine (5.20 ml, 31.46 mmol) in DMF (55 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.40 g, 12.52 mmol) at room temperature. The reaction was stirred for 18 hours and then washed with saturated sodium bicarbonate solution and brine. Organics were extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (0-80% EtOAc/Hex) afforded 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H); 7.58 (m, 4H); 7.44 (m, 2H); 7.34 (m, 3H); 7.14 (m, 2H); 6.78 (d, J=6.80 Hz, 1H); 5.10 (m, 1H); 3.83 (s, 3H); 3.63 (s, 2H); 1.41 (d, J=6.80 Hz, 3H). MS (Electrospray): m/z 347.1 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:54](=[O:62])[NH:55][S:56]([CH:59]([CH3:61])[CH3:60])(=[O:58])=[O:57])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45](O)=[O:46])=[CH:42][C:41]4[CH:48]=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:63][N:64]1[CH2:73][CH2:72][C:67]2([NH:71][CH2:70][CH2:69][CH2:68]2)[CH2:66][CH2:65]1>CN(C=O)C.CO>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:54]([NH:55][S:56]([CH:59]([CH3:61])[CH3:60])(=[O:57])=[O:58])=[O:62])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]([N:71]4[C:67]5([CH2:66][CH2:65][N:64]([CH3:63])[CH2:73][CH2:72]5)[CH2:68][CH2:69][CH2:70]4)=[O:46])=[CH:42][C:41]4[CH:48]=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reactant: CN1CCC2(CCCN2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1CCCC13CCN(C)CC3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
HATU (30 mg, 0.079 mmol) was added to a stirring solution of 13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (34 mg, 0.063 mmol) and 8-methyl-1,8-diazaspiro[4.5]decane (24 mg, 0.16 mmol) in DMF (0.5 mL) and TEA (100 μL, 0.72 mmol) and the reaction mixture was stirred at rt for 1 h (complete by LCMS). The reaction mixture was diluted with MeOH, filtered and purified by preparative HPLC (CH3CN/H2O w/10 mM NH4OAc) to yield 13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (19.7 mg, 0.029 mmol, 46% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ ppm 1.10-2.20 (m, 22H), 2.76 (s, 3H), 2.67-3.49 (m, 9H), 3.91 (s, 3H), 3.86-4.00 (m, 1H), 4.27-4.45 (m, 1H), 5.07-5.20 (m, 1H), 6.91 (s, 1H), 7.03 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.26 (br s, 1H). LC-MS retention time: 2.64 min; m/z 671 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].[Cl-].[NH4+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCO)CC(=O)c1ccc(F)cc1
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: OCCCc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-hydroxyhexane-1,3-dione (38 g, 0.17 mol) in 150 mL ethanol and hydrazine hydrate (17.05 g, 0.34 mol) is added slowly over a 30 min period (exothermic up to 35° C.). The resulting solution is stirred for 1 h at RT then the mixture is added to aqueous ammonium chloride. Extraction with ethyl acetate and evaporation of the organic phase results in the crude product. The product is purified by trituration with 2×200 mL n-hexane and the product is obtained as solid (29 g, 77%).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][C@@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][C@@H:58]5[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 95.0 mg (0.146 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.4 ml of N,N-dimethylformamide, 92.4 mg (0.322 mmol) of (S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate and 54.2 mg (0.392 mmol) of potassium carbonate were added, and the mixture was stirred at 90° C. for 5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-59/41 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 91.3 mg of the title compound as a white solid (yield: 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>C(O)C>[CH2:8]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CNCCN1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN1CCNCC1
Reaction time: 8 h
Yield: 29.2 %

Procedure:
Anhydrous piperazine (19.5 g) was dissolved in ethanol (100 ml), and a solution of 1-bromobutane (24.8 g) in ethanol (50 ml) was added dropwise over a period of 20 minutes at room temperature. After stirring overnight, the reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure. To the residue obtained was added a 40% aqueous solution of sodium hydroxide, and extracted with ether three times. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound (7.53 g) as a yellow oily substance. Yield=29%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[CH:4][CH:3]=1.[CH2:32]=O.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)[C:11]([C:13]2[C:18]([NH:19][CH3:32])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)N(CCc2ccc(Cl)cc2)Cc2ccc(C3CCC3)cc2)n1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1ccc(C)nc1C(=O)N(CCc1ccc(Cl)cc1)Cc1ccc(C2CCC2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A mixture of 3-amino-6-methyl-pyridine-2-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-(4-cyclobutyl-benzyl)-amide (151 mg, 0.348 mmol), 37% aq. formaldehyde solution (0.16 mL, 2.09 mmol) and ethanol (2 mL) was stirred at 50° C. for 3 h, then after removal of volatile material by distillation, sodium borohydride (55 mg, 1.39 mmol) was added, and stirring at 50° C. was continued over 3 h. After cooling, the reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced the title compound (126 mg, 81%). Colourless gum, MS (ISP) 448.3 (M+H)+.
Reaction SMILES: [Br:1]Br.[Br:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC1C=CC=CC=1Cl>[Br:1][C:13]([CH3:14])([CH3:15])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][Br:3])=[CH:7][CH:8]=1)=[O:16]
Reactant: CC(C)C(=O)c1ccc(CCBr)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CC(C)(Br)C(=O)c1ccc(CCBr)cc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A solution of 10 g of bromine in 25 ml of 1,2-dichlorobenzene is added drop wise at room temperature to 13.0 g (0.0509 mol) of crude 1-[4-(2-bromoethyl)phenyl]-2-methylpropan-1-one that is dissolved in 100 ml of 1,2-dichlorobenzene. The reaction mixture is stirred overnight, and then poured into a 5% sodium thiosulfate solution. The mixture is stirred for 30 minutes, and the organic layer is washed with 5% sodium thiosulfate solution, sodium bicarbonate solution, and distilled water. The organic layer is passed through a pad of silica gel and eluted with 9:1 heptane:ethyl acetate to give, after concentration, 7.5 g (55% yield) of 2-bromo-1-[4-(2-bromoethyl)phenyl]-2-methylpropan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:21])[CH2:19][CH3:20]>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 91.1 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8 μL (0.1 mMol) 1-propanoic acid, 13.0 mg (91%) of the title compound were recovered.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:30][CH2:31][O:32][Si](C)(C)C.Cl>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:30][CH2:31][OH:32])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: C[Si](C)(C)OCCCl
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(CCO)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of (2-chloro-ethoxy)-trimethylsilane (1.06 mL, 8.95 mmol). The reaction mixture is stirred for 48 h at 60° C. After cooling to room temperature, aqueous 1M HCl (30 mL) is added and the mixture is stirred at room temperature for 30 min, then washed with water and extracted with ethyl acetate twice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:4) to afford 2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethanol as a solid. 1H NMR (400 MHz, MeOD) δ ppm 2.22 (s, 3H), 3.69 (t, J=5.9 Hz, 2H), 4.18 (t, J=5.8 Hz, 2H), 7.21 (dd, J=8.6, 2.0 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.61-7.67 (m, 1H), 8.01 (dt, J=7.9, 2.0 Hz, 1H), 8.61-8.71 (m, 2H). HRMS (ESI) m/z 287.0953 [(M+H)+ Calcd for C16H16ClN2O: 287.0951].
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[C:16](O)(=O)CC(O)=O.N1C=CC=CC=1.Cl>O>[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])(=[O:12])[CH3:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
A mixture comprising 57.2 g of tetrachlorophthalic anhydride, 25.0 g of malonic acid and 60 ml of pyridine was stirred at 70° to 75° C. for 1.5 hours. After adding 200 ml of water and 200 ml of conc. hydrochloric acid, the mixture was boiled for 10 minutes. After allowing to cool, the precipitate was collected by filtration and dried. The solid product thus obtained was extracted with 600 ml of hot ether. The extract was concentrated and the residue was recrystallized from dilute ethanol. Thus, 25.2 g of 2-acetyl-3,4,5,6-tetrachlorobenzoic acid was obtained. NMR (270 MHz, CDCl3): δ 2.03 (s,3H). IR (KBr) ν (C=O) 1770 cm-1, ν (OH) 3380 cm-1.
Reaction SMILES: C(O[Si](OCC)(OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=1)C.Br[C:28]1[CH:33]=CC=CC=1Br.[I-].[Cs+]>>[CH2:13]([O:12][Si:11]([O:18][CH2:33][CH3:28])([O:15][CH2:16][CH3:17])[C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][C:7]=1[Si:11]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH3:14]
Reactant: CCO[Si](OCC)(OCC)c1cccc([Si](OCC)(OCC)OCC)c1
Reactant: Brc1ccccc1Br
Agent: [Cs+]
Agent: [I-]
Product: CCO[Si](OCC)(OCC)c1ccccc1[Si](OCC)(OCC)OCC

Procedure:
The procedure used for the preparation of 1,3 di(triethoxysilyl) benzene was followed using 1,2 dibromobenzene (100.0 g, 0.424 mg). The product after two distillations was a clear colorless oil (11.9 g, 7%). IR (Neat, CsI, cm-1): 3040 w, 2963 s, 2920 s, 2880 s, 730 w, 1480 w, 1436 m, 1426 w, 1310 w, 1290 w, 1160 s, 1100 vs, 955 s, 780 s, 755 s, 718 m, 700 m, 668 w, 515 m, 484 m. 1H NMR (benzene-d6, 22° C., 300 MHz ): δ 1.21 (t, J=7.2 Hz, 18 H, OCH2CH3), 3.91 (q, J=7.2 Hz, 12H, OCH2CH3), 7.29 (dd, J=5.7 Hz, 2H, C6H4), 8.12 (dd, J=5.7 Hz, 2H, C6H4). 13C{:H} NMR (benzene-d6, 22° C., 75.5 MHz ): δ 18.44 (OCH2CH3), 58.87 (OCH2CH3), 129.25, 137.19, 138.97 (C6H4).