Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=CC=1)(C)C.C(N(CC)CC)C.[C:29]1([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(C1C=CC=CC=1)C#C>[Au].ClC(Cl)C>[C:29]1([C:35]#[C:36][P:37](=[O:41])([O:42][C:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:9])[O:38][CH2:39][CH3:40])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Agent: [Au]
Agent: C#CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(Cc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylbenzene (70 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 3-phenylprop-1-en-2-yl phenylethynylphosphonate (68.9 mg, 71%) which is a title compound.
Reaction SMILES: ClC1C=C(I)C=CC=1N.[C:10]([O:14][C:15]([NH:17][C@H:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]2CC2)=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:33]([O:37]C(N[C@H](C1C=CC(OCCOC2CCCCO2)=CC=1)C(O)=O)=O)([CH3:36])([CH3:35])[CH3:34].C1(CBr)CC1>>[C:10]([O:14][C:15]([NH:17][C@H:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20])=[O:16])([CH3:12])([CH3:11])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC2CC2)cc1
Agent: BrCC1CC1
Agent: Nc1ccc(I)cc1Cl
Product: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 3 except that 2-chloro-4-iodoaniline was used in place of 2-chloro-4-bromoaniline in step 1 and (R)-tert-butoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid was prepared by a similar method as described for the preparation of (R)-tert-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-acetic acid in example 48 except that cyclopropylmethyl bromide was used in place of 2-(2-bromo-ethoxy)-tetrahydropyran.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: OCC1CCNC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(CO)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-pyrrolidin-3-ylmethanol via General Procedure E to give 19.1 mg of 299 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH:6]=1)[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCN)cc1
Yield: 51.6 %

Procedure:
A stirred mixture of 11.8 g (0.033 mole) of 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propoxy]benzoic acid ethyl ester and 2.4 g of 85% hydrazine hydrate in 300 mL of ethanol was heated at reflux temperature for 3 hr. After cooling the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with 450 mL of 2N hydrochloric acid and filtered. The filtrate was basified to pH 11 with potassium carbonate and the mixture was extracted twice with 200 mL portions of methylene chloride. The combined extract was washed with 200 mL of water and the solvent was evaporated under reduced pressure to give 3.8 g of oil that solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1

Procedure:
At 0° C., 3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 28, 0.325 g, 0.629 mmol) is added to methanol saturated with hydrogen chloride gas (7 mL) with stirring. The reaction mixture is allowed to reach rt and stirred there for 24 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (6 mL) and ammonium carbonate (0.593 g, 3.77 mmol) is added. After stirring at rt for 16 h, the reaction mixture is concentrated and the residue obtained is purified by preparative HPLC to afford 3-[6-[4-(6-ammo-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine. 1H NMR (Acetone-d6, 400 MHz) δ 11.32 (br, 2H), 8.88 (br, 2H), 8.72 (m, 2H), 8.40 (s, 1H), 8.25 (m, 2H), 7.95 (m, 2H), 7.83 (m, 1H), 7.65 (m, 5H), 7.45 (m, 4H), 7.14 (d, 1H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 533.1.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+].[ClH:19]>C(O)C.O1CCCC1>[ClH:19].[Br:1][C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1nc2cccc(C)n2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc2nc(C(=O)O)c(Br)n12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 3-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate (0.62 g, 2.2 mmol) in ethanol (3.3 mL) and tetrahydrofuran (3.3 mL) was treated with 1 M sodium hydroxide (6.5 mL, 6.5 mmol) and stirred at 20° C. for 2 h. The reaction mixture was concentrated and the resultant solid was diluted with water, cooled to 0° C., and treated with 1 M hydrogen chloride (8.7 mL, 8.7 mmol) dropwise. The aqueous mixture was concentrated to a solid that was diluted with acetonitrile and reconcentrated (2×) to give the desired product which contained sodium chloride. This material was used without further purification. LCMS for C9H8BrN2O2 (M+H)+: m/z=255.0, 257.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(methoxycarbonylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde (0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.40 (9H, s), 1.80 (1H, m), 2.10 (1H, m), 3.00-3.80 (7H, m), 4.70 (1H, br, s), 7.20 (4H, m). ESI-MS m/z: 383(M+1), UV retention time: 2.91 min.
Reaction SMILES: CN(C)[C:3](=[CH2:11])[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].Cl.[NH2:14]O>CO>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]1[O:5][N:14]=[CH:11][CH:3]=1
Reactant: C=C(C(=O)c1cccs1)N(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Product: c1csc(-c2ccno2)c1
Yield: 93.3 %

Procedure:
A mixture of Compound 3 (18.1 g, 100 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol) in 100 mL of anhydrous methanol was refluxed under nitrogen for 2 hours. The reaction mixture was cooled, concentrated and partitioned between water and dichloromethane. The dichloromethane layer was dried with anhydrous sodium sulfate, filtered and concentrated as to yield compound 4 as a dark yellow-orange oil (14.1 g, 93.3 mmol, 93%). GC/MS, m/z=151 at tR=8.30 min (100%). LC/MS,[M+H]=152.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.CC[N:25](CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:25])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 5-bromo-3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-1H-indole-7-carboxylic acid (1.2 g, 3.22 mmol) in CH2Cl2 (100 mL) was added Et3N (650 mg, 6.44 mmol), TBTU (2.1 g, 6.44 mmol), and NH3/MeOH (10 mL). The mixture was stirred for 2 hours at room temperature. The reaction solution was washed with water, and the organic phase was dried (MgSO4), concentrated, and purified by column chromatography on silica gel, giving 770 mg (65%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[N:18][C:19]=2[NH2:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.O>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][NH:21][C:15]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)=[C:19]([NH2:20])[N:18]=[CH:17][N:16]=2)[CH2:24][CH2:25]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: Nc1ncnc(NCC2CCNCC2)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N1CCC(CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
Into a 20 mL reaction vial was added 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (70.00 mg; 0.19 mmol), sodium bicarbonate (23.49 mg; 0.28 mmol) suspended in THF (3.00 ml) and water (0.30 ml). The mixture was cooled to 0° C. Acryloyl chloride (0.02 ml; 0.22 mmol) was added. The ice bath was left to melt. The reaction mixture was then stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting 0-50% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to afford N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine as a white solid (30.00 mg, 37% yield). HPLC purity: 97%, RT=3.665 min. MS: m/z=430 [M+H]+, RT=1.53 min. 1H-NMR (DMSO-d6) δ 7.93 (s, 1H), 7.40 (t, 2H), 7.21-7.08 (m, 8H), 6.76 (dd, 1H), 6.04 (d, 1H), 5.61 (d, 1H), 5.43 (s, 2H), 4.34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H), 2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[O:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][N:9]=[CH:10]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-c2cnco2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccccc1-c1cnco1
Temperature: 70 °C

Procedure:
5-Phenyloxazole (2.0 g, mmol) in chloroform (50 ml) was cooled to 0° C. using an ice bath. Chlorosulfonic acid 4.8 g (2.7 ml, 3 eq) of was added slowly with stirring. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was then cooled to RT, quenched with ice and extracted with chloroform. The organic layer was washed with cold water, brine and concentrated. The brown solid obtained was purified by column chromatography using 5% ethyl acetate in pet ether as eluent, to yield a yellow solid.
Reaction SMILES: COC1C=CC(C2SC3C=C(OC)C=CC=3C=2)=C(N)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.FC1C=[C:44](C=CC=1OCCN1CCCCC1)[CH2:45][NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[C:61]([O:64][CH3:65])[CH:62]=[CH:63][C:57]=2[CH:56]=1>>[CH2:45]([N:46]([CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[C:61]([O:64][CH3:65])[CH:62]=[CH:63][C:57]=2[CH:56]=1)[CH3:44]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc(-c2cc3ccc(OC)cc3s2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1-c1cc2ccc(OC)cc2s1

Procedure:
Synthesized from 5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenyl]amine (231 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenyl]amine (195 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (170 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:27]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.913 g, 5.74 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.74 mmol) dissolved in water (1.500 mL) was added during 5 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.74 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 2 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (24 mL, 144.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase evaporated to yield a slightly yellow oil. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (1.344 g, 77%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.77-1.85 (m, 1H), 2.10-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.32-2.39 (m, 1H), 3.01-3.08 (m, 1H), 3.37 (ddd, 1H), 3.64 (s, 3H), 4.15 (ddd, 1H), 5.08-5.13 (m, 1H), 5.48 (s, 1H), 7.13-7.20 (m, 3H), 7.27 (t, 2H). MS m/z 303 (M+H)+
Reaction SMILES: O.[C:2]12([CH3:12])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:11].C[C@H]1C[C@@H:18]([OH:20])[C@H:17](C(C)C)CC1>C(O)C>[C:2]12([CH3:12])[C:8]([CH3:9])([CH3:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH2:17][CH2:18][OH:20])[OH:11]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CC1(C)C2CCC1(C)C(O)C2
Solvent: O
Solvent: CCO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
5 l of distilled water is added to 233.3 g of the genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 137 g of Borneol, and 0.5 l of l-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[S:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=1.O>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[S:16][C:15]([CH2:17][NH2:18])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(Oc2cccc(Br)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Oc2cccc(Br)c2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of lithium aluminum hydride (204 mg, 5.39 mmol) in tetrahydrofuran (10 mL) was added a solution of the resulting 5-(3-bromophenoxy)-thiophene-2carbonitrile (1.01 g, 3.59 mmol) in tetrahydrofuran (10 mL), and the solution was stirred at room temperature for 2 hours. Then, lithium aluminum hydride (68 mg, 1.80 mmol) was added, and the solution was further stirred at room temperature for 1 hour. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain a mixture of the title compound and debrominated compound (740 mg) as a pale brown oil. As this mixture cannot be purified, it was used in the next reaction without purification.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O>N1C(C)=CC(C)=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in 2,4,6-collidine (25 mL, distilled) was added distilled water (48 μL, 2.7 mmol, 16 equiv.) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexaneacetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 10 min, the reaction was shown to have reached 100% completion by HPLC peak area. The solution was cooled to room temperature and solvent removed under reduced pressure. Hexane (10 mL) was added to the flask and the precipitated residue collected by filtration and rinsed with hexane to give methyl pyropheophorbide-a (70 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:32])(=[O:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(Br)cc1

Procedure:
4′-Bromo-biphenyl sulfonic acid (5 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue collected was recrystallised from petrol/ethyl acetate to give the title compound as large colourless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:5]=[CH:6][C:7]=1[F:8].[Br-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Dimethyl 2-(3,4-difluorophenyl)piperidine-1,4-dicarboxylate (6.578 g, 21.00 mmol) was dissolved in THF (40 mL) and water (0.800 mL). Lithium bromide (14.59 g, 167.97 mmol) and TEA (11.71 mL, 83.98 mmol) were added and the reaction was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and some solvent evaporated in vacuo. EtOAc (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (150 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and extracted with EtOAc (2×300 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo to yield 2-(3,4-difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (5.66 g, 90%) as a light brown oil. MS m/z 298 (M+H)+.