Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[NH:36][CH:35]=[CH:34]2.CC(N(C)C)=O>ClCCl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:41])[F:42])[NH:36][CH:35]=[CH:34]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1cc2cc[nH]c2cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3C(F)(F)F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (276 mg, 2.0 mmol) and 5-hydroxy-6-trifluoromethylindole (110 mg, 0.55 mmol) and DMA (4.0 ml) were stirred at 95° C. for 1.5 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) to give a partially purified oil. This oil was further purified by high performance column chromatography on octadecylsilane reverse phase silica eluting with acetonitrile/water/trifluoroacetic acid (60/39.8/0.2) to give an oil which was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The dichloromethane layer was evaporated to give 6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline (62 mg, 25%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15]([Mg]Br)C>>[CH2:11]([C:6]1[NH:7][C:8]([C:9]#[N:10])=[C:4]([C:1](=[O:3])[CH2:2][CH3:15])[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CC[Mg]Br
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Product: CCCCc1nc(C(=O)CC)c(C#N)[nH]1
Yield: 51.9 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using ethylmagnesium bromide instead of methylmagnesium bromide, the title compound, melting at 84°-85° C., was obtained in a 51.9% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Yield: 78.4 %

Procedure:
A 4 L 3-neck round bottom flask fitted with a nitrogen inlet and mechanical stirrer was charged with a solution of 5-nitroindazole (80.0 g, 0.49 mol) in tetrahydrofuran (1 L). The mixture was cooled to 0° C. and triethylamine (85.4 mL, 0.61 mol) was added. To the mixture was added pivaloyl chloride (63.4 mL, 0.52 mol) dropwise over a period of 15 minutes. The reaction was allowed to warm to 20° C. over a period of 2 hours. The reaction was filtered and concentrated to a dark red oil. To the oil was added methylene chloride (60 mL). The resulting slurry was stirred vigorously, giving a white precipitate that was isolated by filtration. The solid was dried in a vacuum oven at 40° C. overnight to afford the title compound (95 g, 79%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10]C)=O.[CH:12]1([C:15]#[N:16])[CH2:14][CH2:13]1.[NH4+].[OH-]>O1CCOCC1.O>[CH:12]1([C:15]2[N:16]=[C:8]([OH:10])[C:4]3[S:5][CH:6]=[CH:7][C:3]=3[N:2]=2)[CH2:14][CH2:13]1
Reactant: N#CC1CC1
Reactant: COC(=O)c1sccc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1nc(C2CC2)nc2ccsc12
Yield: 72 %

Procedure:
Dry HCl gas was bubbled through a solution of methyl 3-aminothiophene-2-carboxylate (1.64 g, 10.4 mmol) and cyclopropanecarbonitrile (27 mL) in dioxane (40 mL) for 1 h then the reaction mixture was diluted with cold water (2 volumes), basified with NH4OH (50 mL) and the resulting solid filtered and air dried to give the title compound (1.44 g, 72%) as a white solid: IR νmax (Nujol)/cm−1 2925, 1664, 1597, 788; NMR δH (400 MHz, DMSO) 1.04 (4H, m), 2.00 (1H, m), 7.20 (1H, d J 5.0 Hz), 8.10 (1H, d, J 5.0 Hz) and 12.60 (1H,br).
Reaction SMILES: Cl.[CH3:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9]>>[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([NH:3][CH3:2])=[O:9]
Reactant: CN
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: Cl
Product: CNC(=O)c1ccc(F)c(F)c1
Yield: 75 %

Procedure:
Using methylamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids (Scheme C), the title compound was obtained (75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3 H) 7.55 (dt, J=10.61, 8.34 Hz, 1 H) 7.72 (dddd, J=8.59, 4.55, 2.15, 1.39 Hz, 1 H) 7.86 (ddd, J=11.68, 7.89, 2.15 Hz, 1 H) 8.48-8.59 (m, 1 H). ESI-MS: m/z 172.1 (M+H)+. mp=142.7-145.0° C.
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].CN(C)CCNC(=O)N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1.Cl.C([O:93][C:94]([C:96]1([NH2:99])[CH2:98][CH2:97]1)=[O:95])C>>[C:94]([C:96]1([NH:99][C:2](=[O:3])[NH:1][C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:98][CH2:97]1)([OH:95])=[O:93]
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1(N)CC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NC3(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride was used instead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 657.3 (M+H)+, 4.18 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3-5.3 (1H, m), 4.8 (1H, br. s.), 4.6 (1H, br. s.), 3.7-3.8 (1H, m), 3.6-3.6 (1H, m), 3.5-3.6 (1H, m), 2.5-2.7 (2H, m), 2.4 (1H, dd, J=12.1, 8.4 Hz), 2.2 (1H, dd, J=17.1, 6.4 Hz), 2.0 (1H, d, J=11.9 Hz), 1.9 (2H, dt, J=6.6, 3.2 Hz), 1.8-1.9 (2H, m), 1.7-1.8 (4H, m), 1.4-1.7 (7H, m), 1.4 (3H, td, J=13.1, 4.0 Hz), 1.3 (3H, t, J=11.7 Hz), 1.2 (3H, s), 1.1-1.1 (3H, m), 1.1 (3H, d, J=2.4 Hz), 1.0 (3H, s), 1.0 (2H, s), 0.9 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:12]2[CH:22]=[C:16]3[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]3[C:14](=[O:23])[N:13]=2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(Cl)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 2-(4-chlorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]Br.S(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Oc2cccnc2N)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cc(Br)cnc2N)cc1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
Placed 4-(2-aminopyridin-3-yloxy)benzonitrile (13.95 g, 66.05 mmol) in acetic acid (50 mL) and cooled to 0° C. Slowly added bromine (4.229 mL, 82.56 mmol) and stirred for an hour. The reaction mixture was poured onto saturated sodium bisulfite and ice. Extracted with dichloromethane three times, washed with 2N NaOH, water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (12.7 g, 66.28% yield) as a light yellow solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16]Br)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH:27]([CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:27]([N:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH:15]([OH:18])[C:13]2[N:14]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][CH:12]=2)[CH3:39])=[CH:30][CH:31]=1)([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(CC(C)NCc2ccccc2)cc1
Reactant: O=C(Nc1nc(C(=O)CBr)cs1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(C)N(Cc2ccccc2)CC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.5 g (0.011 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolved in 20 ml of dimethylformamide and added dropwise to a stirred solution, at room temperature, of 2.6 g (0.092 mol) of N-benzyl-2-(4-carbomethoxyphenyl)-1-methylethylamine and 1.1 g (0.011 mol) of triethylamine dissolved in 40 ml of dimethylformamide. After 1.5 hours ice/water is added, and the mixture is extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated. The resulting amino-ketone is taken up in 100 ml of methanol and at room temperature, 0.6 g of sodium borohydride is added. After 1 hour the mixture is evaporated to dryness, water is added, and hydrochloric acid is used to acidify. After 10 minutes the mixture is made alkaline with ammonia and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using toluene/ethyl acetate=8:2 as eluant.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])=[CH:17]1.C([O-])(=O)C.[Na+]>CNC=O>[CH:14]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:15]
Reactant: COC(=O)c1cccc(-c2coc3ccccc23)c1
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CNC=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2c(C=O)oc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of phosphorus oxychloride (3 g) and N-methylformanilide (3 g) was added a solution of methyl 3-(benzofuran-3-yl)benzoate (3 g) in N-methylformamide (1.5 g) at room temperature. The mixture was stirred overnight at room temperature and was poured onto aqueous sodium acetate solution. The product was extracted with ethyl acetate and the organic layer was washed with hydrochloric acid solution, water and brine. The layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1) to afford methyl 3-(2-formylbenzofuran-3-yl)benzoate (2.39 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23])C1C=CC=CC=1>Br.C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>[F:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])=[O:24]
Reactant: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccccc1O)c1ccncc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Title compound 445 (1.99 g, 6.18 mmol) was dissolved in the solution of HBr (33% in AcOH, 15.0 mL) and acetic acid (10.0 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and basified with solid sodium bicarbonate until alkaline. More water was added to dissolve the salt and the aqueous layer was extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was triturated in 30% ethyl acetate in hexanes to afford title compound 446 (1.21 g, 84%) as a beige-yellow solid. 1H NMR (DMSO-d6) δ (ppm): 10.02 (s, 1H), 9.75 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.59 (dd, J=4.8, 1.3 Hz, 1H), 7.94 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=6.1, 4.9 Hz, 1H), 7.03 (ddd, J=8.0, 7.4, 1.6 Hz, 1H), 6.92 (dd, J=8.0, 1.4 Hz, 1H), 6.84 (td, J=7.6, 1.3 Hz, 1H). MS (m/z): 233.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22](O)=[O:23])[CH:15]=[CH:14][C:13]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22]([NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:23])[CH:15]=[CH:14][C:13]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: O=C(NC1CCCc2cc(C(=O)O)ccc21)OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCc2cc(C(=O)Nc3ccncc3)ccc21)OCc1ccccc1
Yield: 33.4 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 7 using 5-(benzyloxycarbonylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (2.50 g), thionyl chloride (2.75 g), 4-aminopyridine (724 mg) and triethylamine (1.55 g), the objective 5-(benzyloxycarbonylamino)-N-(4-pyridyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.03 g) was obtained as colorless crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@@H:13]([CH2:12][NH:30][CH2:27][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCN
Solvent: CC#N
Product: CCCNC[C@@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.7 g, 1.8 mmol), propan-1-amine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (EtOAc/MeOH). Yield: 0.4 g, 73%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 228° C. MS m/z (rel. intensity, 70 eV) 285 (M+, 3), 207 (4), 73 (5), 72 (bp), 70 (5). [α]=+67° (MeOH).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:11][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: OCCN(CCC1OCCO1)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCC1OCCO1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-((2-(1,3-dioxolan-2-yl)ethyl)(benzyl)amino)ethanol (2.81 g, 11.2 mmol) in DMF (10 mL) was added imidazole (1.67 g, 24.61 mmol) and tert-butyldimethylsilyl chloride (3.35 g, 22.39 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated art reduced pressure (3.87 g, 95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:7]1)=[O:4].CCN(CC)CC.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C(O)(C)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:12][CH2:13][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH2:7]1)=[O:4]
Reactant: NCC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reactant: Clc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(CNc1nc2ccccc2s1)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
The mixture of 2-amino-N-[(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]acetamide (0.080 g, 0.25 mmol), Et3N (0.35 mL, 2.5 mmol) and 2-chloro-benzothiazole (0.424 g, 2.5 mmol) in isopropanol was stirred overnight at 90° C. The reaction mixture was concentrated and chromatographed to provide 55 mg of the title compound in 49% yield. MS (EI) calculated: (M+)+=452.2; found: 452.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:20])[CH3:19])#[CH:10]>>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:10]2[N:17]([C:18](=[O:20])[CH3:19])[C:12]3[C:11]([CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][CH:4]=1
Reactant: C#Cc1ccccc1NC(C)=O
Reactant: Cc1ccc(I)cc1
Product: CC(=O)n1c(-c2ccc(C)cc2)cc2ccccc21
Yield: 57 %

Procedure:
The general procedure was used to convert 1-iodo-4-methylbenzene and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 57% yield. 1H NMR (300 MHz, DMSO) δ 8.24-8.22 (d, J=8.2, 1H), 7.61-7.59 (d, J=6.3, 1H), 7.43-7.40 (d, J=8.0, 2H), 7.36-7.24 (m, 4H), 6.71 (s, 1H), 2.37 (s, 3H), 2.07 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.94, 140.70, 138.95, 137.81, 131.53, 130.12, 129.67, 129.64, 125.44, 124.26, 121.31, 116.24, 111.41, 28.41, 21.70. Anal. Calcd. for C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found C, 81.66; H, 6.02; N, 5.62. m.p.: 67-69° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(P(CCCC)CCCC)CCC.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a stirred solution of N-Boc-4-piperidinemethanol (10 g, 46.45 mmol) in dry THF (500 mL) was added tributyl phosphine (18.77 g, 92.9 mmol) and 4-hydroxy benzoic acid methyl ester (10.6 g, 69.67 mmol). The reaction mixture was cooled to 0° C. and ADDP (23.41 g, 92.9 mmol) was added dropwise from an addition funnel over a period of 1 hr. The reaction was gradually brought to room temperature and stirring continued for 1 hr. The sol-vent was removed under vacuum and EtOAc (50 mL) was added and cooled to 0° C. The solid formed was filtered and the clear filtrate concentrated and purified by column chromatography (ISCO) using a step gradient starting with heptane going to EtOAc 100%. Desired fractions were collected and the solvent evaporated in vacuo affording 5.9 g (36%) of 4-(4-methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid t-butyl ester as an oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:44])[CH2:7][CH2:8][NH:9][C:10](=[O:43])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)=[O:30])[CH:18]2[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[CH:13][CH:12]=1)C.CCO.[Li]>O>[O:22]1[C:21]2([CH2:26][CH2:27][CH:18]([CH:17]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][C:39]([F:41])([F:40])[F:42])=[CH:36][CH:37]=3)=[O:30])[C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:44])=[O:5])=[O:43])=[CH:12][CH:13]=3)[CH2:19][CH2:20]2)[O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCC3(CC2)OCCO3)cc1
Agent: [Li+]
Agent: [Li]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCC3(CC2)OCCO3)cc1

Procedure:
180 mg LiOH dissolved in 2.2 mL H2O was added to the entire yield of the above 3-{4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid ethyl ester dissolved in 22 mL abs. EtOH. After 1 hour at 25° C. the solvent was evaporated and 10 mL H2O followed by 500 mg citric acid dissolved in 20 mL H2O was added to the residue affording a pH of 4-5. The resulting product was a mixture of the acid and its lithium salt.