Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])O1>>[OH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Product: O=C(O)CCc1ccc(OCc2cccc(-c3ccccc3O)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. colorless crystals (yield 33%). MS (APCI−): 347 (M−H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Yield: 92.9 %

Procedure:
p-Acetylbenzenesulphonyl chloride (4.0 g, 18 mmol), aqueous dimethylamine (10 ml, 55 mmol), and THF (30 ml) were stirred together for 1 h at 20° C. and then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure and the resulting residue recrystallised from either water or ether to give p-dimethylaminosulphonylacetophenone as fine white needles (3.8 g, 93%) m.p. 98°-99° C. (H2O); δH (dmso-d6) 8.0(4H, ABq, aryl), 2.65(9H, S, 3 x Me).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([S:7](=[O:10])(=[O:9])[NH2:8])[S:4][C:3]=1[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15].[C:17]1([O:23]C(Cl)=O)C=CC=CC=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([NH2:48])[N:39]=1)=[O:37]>C(#N)C>[CH3:34][O:35][C:36]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[C:40]([NH:48][C:17](=[O:23])[NH:8][S:7]([C:5]2[S:4][C:3]([CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])=[C:2]([CH3:1])[CH:6]=2)(=[O:10])=[O:9])[N:39]=1)=[O:37]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)n1
Reactant: CC(=O)OCCc1sc(S(N)(=O)=O)cc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)cc(NC(=O)NS(=O)(=O)c2cc(C)c(CCOC(C)=O)s2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of 0.263 g acetic acid 2-(3-methyl-5-sulfamoyl-thiophen-2-yl)-ethyl ester in 5 ml acetonitrile was added 0.188 g phenylchloroformate and 0.252 g triethylamine at ° C. and the mixture was stirred at this temperature for 2 h. To the resulting suspension was added 0.220 g 6-amino-4-trifluoromethyl-pyridine-2-carboxylic acid methyl ester and the mixture was heated to 60° C. for 18 h. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated. The residue was triturated with t-butylmethylether. The solid was collected by filtration to yield 0.376 g of the title compound as white crystals. MS (ISN) M−H+=508.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:5][CH:4]=1.[CH2:16]([Li])CCC.CI.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[C:5]([CH3:16])[CH:4]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COc1ccc(OC2CCCCO2)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Dissolve 2-(4-methoxyphenoxy)tetrahydro-2H-pyran (20 g, 96 mmol, Preparation 27) in 200 mL anhydrous THF at 0° C. under nitrogen atmosphere. Add n-butyl lithium (n-BuLi) (78 mL, 1.6 M in hexanes, 125 mmol) dropwise via an additional funnel. Stir the resulting mixture at 0° C. for 3 hours. Add CH3I (7.8 mL, 125 mmol) in one batch. After 10 minutes add water. Rotary evaporate off volatiles, extract residue with Et2O and dry to give 21.3 g (100%) of 2-(4-methoxy-2-methyl-phenoxy)tetrahydro-2H-pyran as a yellow oil (21.3 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=8.8 Hz, 1H), 6.75 (d, J=3.0 Hz, 1H), 6.68 (dd, J=8.8, 3.1 Hz, 1H), 5.30 (t, J=3.3 Hz, 1H), 3.96 (ddd, J=12.0, 9.2, 3.1 Hz, 1H), 3.78 (s, 3H), 3.67-3.56 (m, 1H), 2.28 (s, 3H), 2.10-1.96 (m, 1H), 1.94-1.83 (m, 2H), 1.67 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 154.14, 149.33, 128.78, 116.55, 115.79, 111.08, 97.20, 62.15, 55.56, 30.73, 25.38, 19.14, 16.55.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23](Cl)=[O:24])[CH2:18][C:17]2=[O:26]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:24])[CH2:18][C:17]2=[O:26]
Reactant: O=C1CC(C(=O)Cl)c2ccc(Cl)cc21
Reactant: C1CCN(CC2COCCN2)C1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCOCC2CN2CCCC2)c2ccc(Cl)cc21
Yield: 104.6 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.89 g of 3-(pyrrolidin-1-ylmethyl)morpholine, 2.0 ml of triethylamine and 0.91 g of 5-chloro-3-oxoindan-1-carbonyl chloride, to afford 0.83 g of the title compound, melting at 220°-229° C. (dec.).
Reaction SMILES: ClC1N=C2C(N=C(C3([F:16])COC3)N2C)=C(N2CCOC[C@@H]2C)N=1.[Cl:24][C:25]1[N:33]=[C:32]2[C:28]([N:29]=[C:30]([C:36]3(O)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]2[CH2:34][CH3:35])=[C:27]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]2[CH3:49])[N:26]=1>>[Cl:24][C:25]1[N:33]=[C:32]2[C:28]([N:29]=[C:30]([C:36]3([F:16])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]2[CH2:34][CH3:35])=[C:27]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]2[CH3:49])[N:26]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Reactant: CCn1c(C2(O)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Product: CCn1c(C2(F)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound (h-1) was prepared in an analogous fashion to (S)-4-(2-chloro-8-(3-fluorooxetan-3-yl)-9-methyl-9H-pur-in-6-yl)-3-methylmorpholine, using (S)-4-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol as the starting material. 1H NMR (CDCl3, 500 MHz) δ ppm 5.90 to 4.60 (broad s, 2H), 4.37 (q, J=7.1 Hz, 2H), 4.02 (dd, J=11.4 Hz, 3.4 Hz, 1H), 3.98 to 3.86 (m, 4H), 3.78 (dt, J=11.7 Hz, 7.1 Hz, 2H), 3.62 (td, J=11.9 Hz, 2.8 Hz, 1H), 3.48 (d, J=7.0 Hz, 1H), 2.55 to 2.35 (m, 2H), 2.22 to 2.06 (m, 2H), 1.43 (t, J=7.1 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=384 [M+H]+, RT=2.10 min.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>CN(C)C=O.[H-].[Na+]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:26]([C:20]4[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])(=[O:28])=[O:27])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1C=CC(c2c[nH]c3ccc(O)cc23)=CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Yield: 51.1 %

Procedure:
By a method similar to Example 45, using 3-(1-methyl-pyridin-4-yl)-5-hydroxy-1H-indole (1.50 g, 6.5 mmol) in dimethylformamide (40 mL), sodium hydride (0.29 g of a 60% dispersion in oil, 7.2 mmol), 2,6-difluorobenzenesulfonyl chloride (1.52 g, 7.2 mmol) provided 1.35 g (51%) of 2,6-difluorobenzenesulfonic acid 3-(1-methylpiperidin-4-yl)-1H-indol-5-ylester as an off-white solid: mp 235-238° C.; MS(ES+): m/e 407.0 (M+1); 1H NMR (400 MHz, dmso-d6): 11.04 (br s, 1H), 7.92-7.82 (m, 1H), 7.42-7.33 (m, 2H), 7.29 (d, 1H, J=8.8 Hz), 7.15 (d, 1H, J=2.0 Hz), 7.06 (d, 1H, J=2.0 Hz), 6.79 (dd, 1H, J=8.8, 1.8 Hz), 2.78 (br d, 2H, J=11.2 Hz), 2.56-2.46 (m, 1H), 2.16 (s, 3H), 1.93 (br t, 2H, J=11.8 Hz), 1.74-1.64 (m, 2H), 1.60-1.46 (m, 2H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:28][CH:27]=1)[CH3:25]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 37.5 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-ethylaniline (40.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.7 mg).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:4]([NH2:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][CH:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 1,3-dihydro-1-methyl-3(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenyl isocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([O-])=O.[N+](C1C=CC=CC=1C=CC1C=CC=CN=1)([O-])=O>>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=Cc2ccccn2)c1
Agent: O=[N+]([O-])c1ccccc1C=Cc1ccccn1
Product: COc1ccc(N)c(CCc2ccccn2)c1

Procedure:
Reduction of 2-(2-nitro-5-methoxystyryl)pyridine as described in Example 2 (a) for 2-(o-nitrostyryl)pyridine provides 2-(2-amino-5-methoxyphenethyl)pyridine having a melting point of 77.5°-78.5° C. (corr.) as the monohydrate obtained by crystallization from isopropyl acetate-ethanol-water.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[OH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[O:15][CH:16]1[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(Oc2cnccn2)C1

Procedure:
Compound P22 was prepared according to the general procedure described for the synthesis of P21 in Preparation 21, using 2-chloropyrazine in place of 2-bromopyridine, to afford P22. LCMS (ESI) m/z 252.4 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.97 (m, 2H), 4.32 (m, 2H), 5.30 (m, 1H), 8.03 (dd, J=2.5, 1.2 Hz, 1H), 8.16 (d, J=2.5 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H). Compound P22 was deprotected with trifluoroacetic acid as described for tert-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19 in Example 3, before being used in the coupling step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH2:23])C.[CH2:29](N(CC)CC)C.C(OCC)(=O)C>O1CCOCC1.O>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:4]=[CH:3][C:2]=1[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH3:29])=[C:19]([O:18][CH3:16])[CH:20]=1
Reactant: CCOC(=O)Cn1ncc(Br)c(Br)c1=O
Reactant: CCN(CC)CC
Reactant: CCOc1cc(CN)ccc1OC
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ncc(NCc2ccc(OCC)c(OC)c2)c(Br)c1=O
Yield: 98 %

Procedure:
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate (500 mg, 1.47 mmol) and 3-ethoxy-4-methoxybenzylamine (960 mg, 4.41 mmol) in 1,4-dioxane-water (1:1, 5 mL) were stirred with triethylamine (0.615 mL) at 100° C. for 2.5 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The resulting residue was purified by silica gel chromatography (chloroform/2-propanol=20/1) to give the desired product (640 mg, 98% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1)#[CH:29]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:29]#[C:28][C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)C1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (81.5, 54%); 1H NMR δ (CDCl3): 7.8 (d, J=8.05 Hz, 1H), 7.4-7.19 (m, 8H), 6.37-6.3 (m, 1H), 5.6 (s, 2H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 312.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>N1C=CC=CC=1.CCOC(C)=O.[Pd].[Cu-]=O>[OH:18][CH2:13][CH2:14][CH2:15][C:16]1[O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:17]=1
Reactant: C#CCCCO
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: O=[Cu-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc2oc(CCCO)cc2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
See Fancelli D.; Fagnola, M. C.; Bedeschi, A. Solid phase Synthesis of 2-Substituted Benzofurans via the Palladium-catalyzed Heteroannulation of acetylenes. Tetrahedron Letters 1997, 38, 2311-2314. A mixture of methyl 4-hydroxy-3-iodobenzoate (93) (35 g, 125.9 mmol), 4-pentyn-1-ol (11.00 g, 130.7 mmol) and copper (I) oxide (12.62 g, 88.2 mmol) in dyr pyridine (150 mL) was stirred at 100-120° C. overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc (200 mL), filtered through a Celite pad (5 cm) and concentrated. The residue was dissolved in EtOAc (300 mL), washed with 2 M HCl (50 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. Column chromatography (SiO2, EtOAc/hexanes, 1/1) followed by recrystallization (hexanes/diethyl ether, 2/1) afforded 95 as light yellow crystals (14.39 g, 49%). 1H NMR (DMSO-d6) δ8.20 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.74 (s, 1H), 4.59 (b, 1H), 3.49 (b, 2H), 3.86 (s, 3H), 2.84 (t, J=7.1 Hz, 2H), 1.85 (m, 2H). HPLC (method B) tR 4.20 min (100.00 area %).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CN(C2CCNCC2)C1
Yield: 79 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.75 g, 8.88 mmol) in dichloroethane (80 mL) was added azetidine (0.6 g, 10.53 mmol) and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resulting solution was stirred at RT for 18 h. The reaction mixture was partitioned between water and DCM and the layers separated. The organic layer was extracted further with DCM and the combined aqueous layers were concentrated in vacuo. The resultant white semi-solid was suspended in DCM and a saturated aqueous solution of NaHCO3 was added. The layers were thoroughly mixed, the organic layer isolated and the aqueous layer further extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.0 g, 95%). BOC-deprotection of 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.67 mmol) using TFA:DCM (1:4) gave the title compound as a yellow oil (185 mg, 79%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37].[Li]C1C=CC=CC=1>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])=[N:11][C:12]([N:16]2[C:17]([CH3:22])=[CH:18][CH:19]=[C:20]2[CH3:21])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)cc(C)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 906 mg (2.95 mmol) of 3-(benzyloxy)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2,4-dimethylpyridine in 20 mL of anh. THF were added 789 mg (2.95 mmol) of 1-bromo-9-(methoxymethoxy)nonane followed by 1.99 mL (3.54 mmol) of a 1.80 M solution of PhLi in hexane. The reaction mixture was stirred at −78° C. for 30 min. then the reaction mixture was warmed to 23° C. slowly, and the reaction mixture was stirred 30 min. The reaction was quenched with satd aq ammonium chloride and then poured into 80 mL of water. The mixture was then extracted with two 80-mL portions of ethyl acetate. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as a light yellow oil: yield 877 mg (60%); silica gel TLC Rf 0.3 (9:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.18-1.22 (br m, 12H), 1.50 (quint, 2H, J=6.8 Hz), 1.65 (m, 2H), 2.06 (s, 6H), 2.26 (s, 3H), 2.75 (dd, 2H, J=7.6, 7.6 Hz), 3.28 (s, 3H), 3.43 (t, 2H, J=6.8 Hz), 4.53 (s, 2H), 4.82 (s, 2H), 5.78 (s, 2H), 6.79, (s, 1H) and 7.29-7.40 (m, 5H); 13C NMR (CDCl3) δ 13.30, 13.30, 16.35, 26.19, 28.92, 29.40, 29.48, 29.50, 29.55, 29.61, 29.73, 32.13, 55.05, 67.86, 75.24, 96.36, 106.40, 106.40, 121.68, 121.68, 127.73, 127.90, 127.90, 128.89, 128.89, 138.83, 141.97, 141.97, 146.80, 150.76 and 155.88; mass spectrum (APCI), m/z 493.3426 (M+H)+ (C31H45N2O3 requires 493.3430).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:41][CH2:40]2)=[O:38])=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl.CO>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:40][CH2:41]2)=[O:38])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1coc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2nc(C(=O)O)co2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 2-{[6-(4-cyanophenyl)-5-(cyclopropylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}-1,3-oxazole-4-carboxylate (Example 43) (50 mg, 0.09 mmol) in tetrahydrofuran (1.5 ml) is added a solution of lithium hydroxide (4.24 mg, 0.18 mmol) in water (1.5 ml). The reaction solution is stirred at room temperature overnight (16 h). The pH of the solution is adjusted to less than pH 7 with 1 N hydrochloric acid (500 μl). After 5 minutes stirring, a precipitate is obtained. Methanol (3 ml) is added, and the crude reaction solution is purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10). The title compound is isolated as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][CH:24]=[CH:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=O)[C:29]2=[CH:28][CH:27]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:34]1[C:29]2[C:30](=[N:31][C:26]([CH:25]=[CH:24][O:23][CH3:22])=[CH:27][CH:28]=2)[CH2:32][O:33]1
Reactant: COC=Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (176 mg, 1.16 mmol) in THF (5 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (2.3 mL of a 1 M solution in THF, 2.3 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 2-(2-methoxy-vinyl)-7H-furo[3,4-b]pyridin-5-one (111 mg, 0.58 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and is poured into cold 10% aqueous HCl solution (30 mL) at 0° C. The resulting mixture is stirred at 50° C. for 1 h and room temperature overnight. The solid which formed is collected by filtration and dried to give the title compound as a light brown solid (65 mg, 35%).
Reaction SMILES: [C:1](O)(=O)[CH3:2].C[SiH](C)C.[C:9]([BH3-])#N.[Na+].Cl.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20]([NH2:22])=[O:21]>CO>[CH:2]1([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH:15]2[C:20]([NH2:22])=[O:21])[CH2:1][CH2:9]1
Reactant: [BH3-]C#N
Reactant: NC(=O)C1COCCN1
Reactant: CC(=O)O
Agent: C[SiH](C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1COCCN1C1CC1
Temperature: 70 °C
Yield: 47.3 %

Procedure:
2.9 g of molecular sieve 3A, 4.3 g (72 mmol) of acetic acid, 7.6 g (43.2 mmol) of 2(1-ethoxy-cyclopropyl)oxy]trimethylsilane and 4.4 g (31.7 mmol) of sodium cyanoborohydride are added successively to 1.2 g (7.2 mmol) of morpholine-3-carboxylic acid amide hydrochloride (WO2005026156 Hennequin L. F. A. et al.) in solution in methanol (36 ml). The reaction mixture is heated at 70° C. for 3.5 hours, then cooled to room temperature and filtered. The filtrate is concentrated under reduced pressure, then the residue is taken up in dichloromethane (200 ml) and washed 3 times with an aqueous solution of NaOH (1N) (100 ml). The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure. 0.58 g of product is obtained, in the form of a white powder. Yield 47%. Melting point 116° C. MH+: 171 (Tr: 1.03 min, condition 2).