Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])[CH:5]=[CH:6][C:7]=1[OH:8].[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:26]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)c(F)c2)C(O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1F

Procedure:
A solution of 0.069 g of benzyl 4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate in 5 ml of acetone is admixed with 0.034 g of potassium carbonate and 0.019 ml of dimethyl sulphate. The reaction mixture is stirred at reflux over 5 hours, cooled and filtered through Hyflo. The filtercake is washed with 2×5 ml of acetone and the filtrate is concentrated by evaporation. The residue is taken up in 30 ml of tert-butyl methyl ether, washed with 10 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=4.32.
Reaction SMILES: COC(OC)C[C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](N)=[O:8].[NH+:16]1C=CC=[CH:18][CH:17]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C1C=CC=CC=1>[N:13]1[C:5]2[N:16]=[CH:17][CH:18]=[C:7]([OH:8])[C:6]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(Cc1ncccc1C(N)=O)OC
Reactant: c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccccc1
Product: Oc1ccnc2ncccc12

Procedure:
The product from Example 228c (1.36 g, 6.47 mmol) was dissolved in benzene (35 ml) and to this solution was added pyridinium-para-toluenesulfonate (0.20 g, 0.8 mmol). The mixture was heated to reflux for 23 h then concentrated under vacuum to give the title compound in quantitative yield sufficiently pure for use as isolated.
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH:18]([CH3:20])[CH3:19])[NH:5][S:6]([NH:9][C@H:10]([C:14](OC)=O)[CH:11]([CH3:13])[CH3:12])(=[O:8])=[O:7].S(N)(N)(=O)=O>CCN(CC)CC>[S:6]([NH:9][C@@H:10]([C:11]1[CH:13]=[CH:14][CH:10]=[CH:11][CH:12]=1)[CH3:14])([NH:5][C@@H:4]([C:18]1[CH:20]=[CH:18][CH:4]=[CH:3][CH:19]=1)[CH3:3])(=[O:8])=[O:7]
Reactant: COC(=O)[C@@H](NS(=O)(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Agent: NS(N)(=O)=O
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)N[C@H](C)c1ccccc1)c1ccccc1
Yield: 63 %

Procedure:
In a procedure similar to the preparation of sulfamide (8b), (R)-phenethylamine (471 mg, 501 μL, 3.84mmol) was subjected to sulfamide formation conditions (SO2Cl2, Et3N, CH2Cl20° C.-RT, 8 h). Flash chromatography (SiO2, Hexanes/EtOAc) yielded 356 mg (63%) of sulfamide (8e) as a white solid. mp=96-97° C.; TLC Rf=0.37 (3:1 Hexanes/EtOAc); [α]25D=−31.2 (c=1.02, CHCl3); 1H NMR (CDCl3, 400 MHZ) δ7.27-7.21 (m, 6H), 7.17-7.14 (m, 4H), 4.74 (s, 2H), 4.43 (dq, J=12.2. 6.2 Hz, 2H), 1.46 (d, J=6.8Hz, 6H); 13C NMR (CDCl3, 100 MHZ) δ142.7, 128.6, 127.5, 126.1, 53.7, 23.6; FTIR(neat) 3312,3032,2992,2944,1603,1493,1454,1381,1320,1149,751,701 cm−1; HRMS (M+H)+ calculated for C16H21N2O2S 305.1324, found 305.1322.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[O:16][C:17]2[C:18]([N:28]=1)=[C:19]1[C:24](=[CH:25][CH:26]=2)[CH:23]([CH3:27])[NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]5[O:16][C:15]([CH3:14])=[N:28][C:18]5=4)[CH:23]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1nc2c3c(ccc2o1)C(C)NCC3
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1nc2c3c(ccc2o1)C(C)N(C(=O)c1cc2ncc(Br)cn2n1)CC3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-6,7,8,9-tetrahydro-3-oxa-1,7-diaza-cyclopenta[a]naphthalene to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][CH:22]=O)[CH2:15]2)[C:3]=1[C:4]([O:6]C)=[O:5].[C:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][CH2:22][NH:33][CH2:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCCc1ccccc1
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCC=O)C1
Solvent: CO
Product: Cc1cccc(CO[C@@H]2CCC[C@H](OCCNCCCc3ccccc3)C2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg of methyl 2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxy-methyl]benzoate and 90 μl of 3-phenylpropylamine are dissolved in 5 ml of methanol. 300 mg of 4 Å molecular sieve, which had been dried by heating, are added, and the mixture is stirred at room temperature for two hours. 25 mg of sodium borohydride are then added to the reaction mixture. After 30 minutes, 50 ml of ethyl acetate are added and the molecular sieve is removed from the mixture by filtration through celite. The filtrate is concentrated under reduced pressure, the residue is dissolved in 5 ml of tert-butanol and 0.5 ml of 10 N potassium hydroxide solution are added. The mixture is refluxed for 1 day. After addition of 2 ml of water, the organic phase is removed and the aqueous phase is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvents are then removed under reduced pressure. This gives 160 mg of 2-methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxymethyl}benzoic acid as a yellow oil. C26H25NO4 (425.57), MS(ESI): 426 (M+H+).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([CH:15]=[N:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2)([OH:14])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C([O-])(O)=O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:27][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[NH:16][CH:15]2[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]([CH3:6])([CH3:7])[CH2:4][C:3]2([C:2]([F:1])([F:28])[F:29])[OH:14])[N:22]=1
Reactant: Cc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(NC3c4ccccc4C(C)(C)CC3(O)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
5.1 ml of a 1 M titanium tetrachloride-CH2Cl2 solution is added in drops to a solution of 111 mg of 1,1,1-trifluoro-4-phenyl-2-[(2-methylquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol in 84 ml of CH2Cl2 at −78° C. After 1 hour at −78° C., the batch is mixed with saturated NaHCO3 and heated to room temperature. The phases are separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 94 mg of product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[CH:36]=[N:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:39]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[O:40])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3cn[nH]c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and 1H-pyrazole-4-carboxylic acid as a colorless oil (95%). HPLC, Rt: 5.15 min (Purity: 69.2%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>>[CH:15]1([CH:11]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[OH:12])[CH2:17][CH2:16]1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Reactant: Br[Mg]C1CC1
Product: OC(c1ccc(-c2ccccc2)nc1)C1CC1

Procedure:
Synthesized using compound 43b (227 mg, 1.24 mmol) and cyclopropylmagnesium bromide (4.96 mL, 2.48 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Light yellow solid. Yield: 234 mg, 84%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.35-0.44 (m, 1H), 0.49 (dq, J=9.4, 4.7 Hz, 1H), 0.55-0.68 (m, 2H), 1.21 (qt, J=8.1, 5.0 Hz, 1H), 3.00 (br, s, 1H), 4.05 (d, J=8.2 Hz, 1H), 7.38-7.44 (m, 1H), 7.44-7.50 (m, 2H), 7.66-7.70 (m, 1H), 7.80-7.85 (m, 1H), 7.94-8.00 (m, 2H), 8.64-8.69 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=2.8, 3.6, 19.0, 75.9, 120.3, 126.8, 128.7, 128.8, 134.5, 137.7, 139.1, 147.6, 156.5; MS (ESI): m/z=226.28 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][OH:16])[C:7]([C:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: OCCNCCO
Reactant: O=C(O)C1=CC=CCC1
Product: O=C(C1=CC=CCC1)N(CCO)CCO

Procedure:
Using the same procedures as those in Example 5 as well as 1,3-cyclohexadiene-1-carboxylic acid and diethanolamine as a starting material, there was obtained 1,3-cyclohexadiene-1-carboxylic acid N,N-bis (2-hydroxyethyl)amide.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2([CH2:37][C:38]([OH:40])=O)[CH2:12][N:13]([CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][C:19]5[CH2:36][C@:26]6([C:34]7[C:29](=[N:30][CH:31]=[CH:32][CH:33]=7)[NH:28][C:27]6=[O:35])[CH2:25][C:20]=5[CH:21]=4)[N:16]=3)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]=[C:2]1[CH2:11][C:10]2([CH2:37][C:38](=[O:40])[N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:12][N:13]([CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][C:19]5[CH2:36][C@:26]6([C:34]7[C:29](=[N:30][CH:31]=[CH:32][CH:33]=7)[NH:28][C:27]6=[O:35])[CH2:25][C:20]=5[CH:21]=4)[N:16]=3)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1
Reactant: O=C(O)CC12CC(=O)Nc3cccc(c31)N(Cc1ccc3cc4c(cc3n1)C[C@]1(C4)C(=O)Nc3ncccc31)C2
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1CC2(CC(=O)N3CCCC3)CN(Cc3ccc4cc5c(cc4n3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1

Procedure:
A mixture of [4-oxo-1-{[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2-yl]methyl}-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl]acetic acid, diastereomer A (50 mg, 0.094 mmol, described in Example 2), pyrrolidine (20 mg, 0.282 mmol), EDC (22 mg, 0.113 mmol), HOBT (17 mg, 0.113 mmol), and N,N-diisopropylethylamine (0.082 mL, 0.470 mmol) was stirred in DMF (0.5 mL) at ambient temperature for 18 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (10 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=585 (M+1). HRMS: m/z=585.2620; calculated m/z=585.2609 for C35H33N6O3.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:25]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:24]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C@H:23]1[O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C@@H:25]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@H:24]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C@H:23]1[O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCCCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCCCCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of (5-(((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)pentyloxy)(tert-butyl)diphenylsilane (28, 664 mg, 0.626 mmol) from Step 1 in tetrahydrofuran (8 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.9 mL, 1.88 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus (silica gel, 10 to 60% tetrahydrofuran in hexanes) to yield the title compound (29, 479 mg, 0.583 mmol, 93%) as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.Cl>C(O)C>[ClH:12].[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:11])=[CH:5][CH:6]=3)=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CNC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CNC(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
A mixture of 0.1 mole of N-methyl-p-aminobenzamide, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 10 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is stirred at about 25° C. for 30 minutes. A precipitate begins to form, and the mixture is then heated at reflux for 4 hours. The mixture is cooled and filtered to obtain p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[CH2:34]Br>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:34][C:26]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:25]=3[Br:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Reaction time: 1.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl) phenyl]-4-methyl-1,3-oxazolidin-2-one (5.3 g, 16.95 mmol) in THF (100 mL) at 0° C., NaH (746 mg, 60 w/w % in mineral oil, 18.65 mmol, 1.1 eq.) was added in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (100 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (5.0 g, 16.95 mmol) in THF (25 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to ambient. The reaction was completed in 1.5 h. The reaction was quenched with sat. aqueous NH4Cl (100 mL). Crude mixture was extracted with EtOAc, and dried over Na2SO4. The resulting clear gel was purified by SiO2 (Biotage 40M cartridge, EtOAc/hexane, gradient, 25% to 45%). The titled compound was obtained as a crystalline solid. LC-MS: 529.11 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.24 (d, J=2.5 Hz, 1H), 8.07 (dd, J=8.7, 2.8 Hz, 1H), 7.91 (s, 1H), 7.79-7.83 (m, 3H), 5.82 (d, J=7.8 Hz, 1H), 4.82 (d, J=16.2 Hz, 1H), 4.44 (d, J=16.3, 1H), 4.11-4.20 (m, 1H), 0.84 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].CN(C=O)C.N1C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2=[N:9][CH:10]=[CH:11][C:6]([C:4]3[CH:5]=[N:1][N:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]#[N:24])[CH:3]=3)=[C:7]2[CH:14]=[CH:13]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(-c4cccc(C#N)c4)c3)ccnc21
Temperature: 125 °C
Yield: 75.2 %

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.025 g, 0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g, 0.00016 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL, 0.00024 mol) were added. The reaction was heated in an open tube to 125° C. for 40 minutes, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile (0.025 gm, 92%) as an oily residue, LC/MS (M+H)+: 316.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:6]1([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:5]2.Br[CH2:18][C:19]([OH:21])=[O:20].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:6]1([CH2:11][CH2:10][N:9]([CH2:18][C:19]([OH:21])=[O:20])[CH2:8][CH2:7]1)[CH2:5]2
Reactant: O=C1c2ccc(F)cc2CC12CCNCC2
Reactant: O=C(O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)CN1CCC2(CC1)Cc1cc(F)ccc1C2=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A stirred solution of 5-fluorospiro[indene-2,4′-piperidin]-1(3H)-one (160 mg, 0.626 mmol), bromoacetic acid (113 mg, 0.813 mmol) and triethylamine (0.436 mL, 3.13 mmol) in acetonitrile (2 mL) was heated at 80° C. for 3 h, then cooled to 25° C. The reaction mixture was diluted with 20 mL of ethyl acetate and washed with 5 mL of water, dried over Na2SO4 and concentrated to dryness without any further purification to give the title compound (174 mg, 0.626 mmol, 100% yield). MS calculated for C15H17FNO3 278.3. found (ESI) m/z 278.4 (M+H)+, retention time 0.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21](O)=[O:22])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:64][C:65]1([OH:70])[CH2:69][CH2:68][NH:67][CH2:66]1>ClCCl>[OH:70][C:65]1([CH3:64])[CH2:69][CH2:68][N:67]([C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]([CH3:20])([CH3:19])[CH2:17]3)=[O:22])[CH2:66]1
Reactant: COc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: CC1(O)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C2Nc3ccc(C(=O)N4CCC(C)(O)C4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.32 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (243 mg, 0.64 mmol) and triethyl amine (0.36 mL, 1.28 mmol) in dichloromethane was added 3-methyl-pyrrolidin-3-ol (66 mg, 0.38 mmol) at room temperature and stirred at room temperature for overnight. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (3-hydroxy-3-methyl-pyrrolidin-1-yl)-[2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]-methanone (63 mg, 50%) as a white foam: LC/MS m/e calcd for C24H30N2O3 (M+H)+: 395.52, observed: 395.2.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]4[CH:28]=[CH:29][S:30][C:26]=4[CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].CCOC(C)=O>CO>[ClH:32].[ClH:32].[ClH:32].[S:30]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:27]=2[CH:28]=[CH:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.2 g, 3 mmol) was treated with 1 N HCl in EtOAc (40 ml, 40 mmol) and MeOH (0.74 ml) and the resulting mixture was stirred 4 h at room temperature. A white precipitate was formed that was collected by filtration and washed with EtOAc. The solid was dried over night under high vacuum to yield trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride as a white powder (1.2 g, 94%), MS (ISP) m/z=345.1 [(M+H)+].
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[N:15]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:15]1[CH:16]1[CH2:19][O:18][CH2:17]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO[Si](C)(C)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCC1CNCCN1C1COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (714 mg, 1.847 mmol) was taken up in DCM (8 mL) and TFA (2.85 mL, 36.9 mmol) was added. The reaction was stirred at rt for 30 min. The solvent was removed in vacuo and the material was dissolved in MeOH. The solution was loaded onto an SCX column (3×5 g, benzenesulfonic acid sorbent) and the columns were flushed with MeOH, then 7N NH3/MeOH to release the product. (+/−) 2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(oxetan-3-yl)piperazine (517 mg) was obtained as a yellow oil.