Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.O=P(Cl)(Cl)Cl.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=3)=[O:33])=[C:18]([CH:29]([CH3:31])[CH3:30])[N:19]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][C:14]=1[F:44]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:22]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([F:44])=[C:13]([NH:12][C:2]3[CH2:3][CH2:4][CH2:5][N:1]=3)[CH:21]=2)[C:17]([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=2)=[O:33])=[C:18]1[CH:29]([CH3:30])[CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCCN1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3=NCCC3)cc2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 2-pyrrolidinone (47 mg, 0.55 mmol) and POCl3 (0.10 ml, 1.1 mmol) was stirred at 0° C. to room temperature for 2h. To the above mixture was then added a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 50 mg, 0.11 mmol) in toluene (3 ml). The reaction was heated to 110° C. for 16 h and was cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase chromatography on C18 bonded silica gel (MeOH) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@@H:7]([O:9]CC2C=CC=CC=2)[C@@H:6]([O:17]CC2C=CC=CC=2)[C@@:5]1([CH3:33])OCC1C=CC=CC=1)(=[O:3])[CH3:2].C([OH:36])C.Cl>[Pd].CO>[C:1]([N:4]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([OH:17])[C@H:5]1[CH2:33][OH:36])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)N1C[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)N1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-1-acetyl-3,4-dibenzyloxy-2-benzyloxy-methylpyrrolidine (Compound 12) (0.595 g, 1.3 mmol), ethanol (30 ml), methanol (10 ml), 10% Pd/C (0.10 g) and a catalytic amount of 1M hydrochloric acid. Purification of the product on silica gel (Eluent: Ethyl acetate/methanol (1:1)) afford-ed(2R,3R,4R)-1-acetyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine(0.2g,yield: 86%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=[O:17])[C:11](=[O:21])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.O.O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[C:11](=[O:21])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CN1CCN(c2ccc(C#N)cc2)CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(N2CCN(CC(=O)O)C(=O)C2)cc1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
Ethyl 2-[4-(4-cyanophenyl)-2-oxopiperazino]-acetate (20.7 g, 72 mmol) is dissolved in 80 ml of methanol, 80 ml of tetrahydrofuran and 100 ml of water, and lithium hydroxide monohydrate (4 g, 98 mmol) is then added. Stirring is continued for 20 minutes and the organic solvent is then removed under vacuum. About 100 ml of water are added to the suspension obtained and this mixture is acidified. The product is filtered off, rinsed with water and dried under vacuum at 50° C. to give 18.5 g of a beige-coloured powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][C@H:3]1[OH:29].[NH2:30][C:31]1[C:39]([C:40]#[N:41])=[CH:38][C:34]([C:35](O)=[O:36])=[C:33]([OH:42])[CH:32]=1.ClC(Cl)Cl.C(O)(=O)C>O>[OH2:12].[NH2:30][C:31]1[C:39]([C:40]#[N:41])=[CH:38][C:34]([C:35]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][C@H:3]2[OH:29])=[O:36])=[C:33]([OH:42])[CH:32]=1
Reactant: N#Cc1cc(C(=O)O)c(O)cc1N
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cc(C#N)c(N)cc2O)[C@H](O)C1
Yield: 10 %

Procedure:
To a stirred solution of 3.95 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide and 1.78 parts of 4-amino-5-cyano-2-hydroxybenzoic acid in 150 parts of trichloromethane were added 3.1 parts of N,N'-methanetetraylbis[cyclohexanamine] and stirring was continued over weekend at room temperature. The reaction mixture was acidified with an acetic acid solution in water. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was taken up in acetonitrile and the precipitate was filtered off. The filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.55 parts (10%) of trans-4-[(4-amino-5-cyano-2-hydroxybenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide monohydrate; mp. 211.4° C. (compound 42).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][OH:14])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(OCC)(=O)C>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:1][CH2:2][CH3:3])(=[O:25])=[O:24]
Reactant: CCCOc1ccccc1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 3-(2-propoxyphenyl)-1-propanol (729 mg) dissolved in THF (35 ml) were added at 0° C. triethylamine (1.57 ml) and methanesulfonyl chloride (0.44 ml). The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][O:36][CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50](O)=[O:51])=[CH:44][CH:43]=1)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.O>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:50](=[O:51])[CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:41])=[CH:43][CH:44]=1
Reactant: COCCNC(=O)c1ccc(CCC(=O)O)cc1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
A solution of (E)-benzyl 3-(4((2-methoxyethyl)carbamoyl)phenyl)acrylate (1.0 g, 3.38 mmol) in ethanol (50 ml) is hydrogenated over 10% Pd/C (100 mg) at 50 psi for 24 h. The catalyst is removed by filteration and the solvent removed under vacuum to give 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid as a clear oil that solidifies on standing. MS (ESI) 251 (M+), 1H NMR (CDCl3); 1.24 (t, 3H, J=6.8 Hz), 2.686 (t, 2H, J=7.2 Hz), 3.00 (t, 2H, J=7.2 Hz), 3.39 (s, 3H), 3.57 (t, 2H, J=5.2 Hz), 3.63 (t, 2H, J=5.2 Hz), 3.69-3.74 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz). A mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (400 mg, 0.8 mmol), 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid (251 mg, 1.0 mmol) and TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (321 mg, 1.0 mmol) and diisopropyl amine (0.42 ml) are dissolved in DMF (20 mL) and stirred for 12 h at 23° C. The mixture was poured into water and extracted with ethyl acetate (3×, 50 mL). The ethyl acetate layer is washed with saturated sodium bicarbonate, 1 N HCl then dried over sodium sulfate and concentrated to give a tan oil. The oil was purified by silica gel chromatography using 10% methanol in dichloromethane with 0.1% NH4OH as eluant to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-(2-methoxyethyl)benzamide (1) as a tan solid, 250 mg (43%). MS (ESI) 733 (M+); 1H NMR (CDCl3) 2.53 (d, 2H, J=6.8 Hz), 2.89 (d, 2H, J=6.8 Hz), 3.23 (s, 3H), 3.37 (s, 3H), 3.54-3.55 (m, 2H), 3.56-3.62 (m, 2H), 4.21 (s, 3H), 5.29-5.28 (m, 2H), 5.67 (s, 2H), 6.31-6.37 (m, 1H), 6.42-6.55 (m, 1H), 6.75-6.85 (m, 2H), 6.89-6.92 (m, 1H), 7.02-7.08 (m, 1H), 7.15-7.28 (m, 6H), 7.45-7.46 (m, 1H), 7.51-7.59 (m, 1H), 7.67-7.69 (m, 1H), 8.55-8.58 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[S:13][C:14]([CH3:20])=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CCN(CC)CC.O>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[S:13][C:14]([CH3:20])=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)=[O:25]
Reactant: COc1ccc(Nc2nc(C(=O)O)c(C)s2)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
A mixture of 2.74 g (9.3 mmol) 2-(3,4-Dimethoxy-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 1.95 ml (14 mmol) 2,4-Dichlorobenzoyl chloride and 3.88 ml (27.9 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 5 min and 50 ml water was added and the mixture was stirred at room temperature for 16 h. After removal of all volatiles the residue was extracted with DCM and evaporated under reduced pressure to yield 4.18 g of amorphous light brown solid which was used without further purification in the consecutive step. MS (m/e): 467.2 (MH+, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[NH2:6])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[BrH:19].[CH2:9]([O:8][CH:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]([NH:6][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCCCOC(OCCCC)C(N)C(=O)OCC
Product: Br
Product: CCCCOC(OCCCC)C(NCCCCCCC(=O)OCC)C(=O)OCC
Temperature: 100 °C

Procedure:
A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g) was heated under nitrogen in a bath at 100° C. for 3 hours. to give crude ethyl 7-((2,2-dibutoxy-1-ethoxycarbonyl-ethyl)amino)heptanoate hydrobromide. A stirred solution of 3.28 g of this hydrobromide in ethanol (13 ml) was cooled in ice-water and treated with a solution of potassium cyanate (1.34 g) in water (4ml), followed by 2N-aqueous hydrochloric acid (3.63 ml); the cooling bath was removed and stirring was continued at room temperature for 22 hours. The ethanol was evaporated in vacuo, the residue was shaken with water and ether, and the ethereal solution was separated, washed with water and dried over magnesium sulphate (MgSO4); removal of the ether left an oil which was heated under nitrogen at 100° C. for 3 hours, to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g). This was stirred in ether (6ml) with water (48 ml) and N-aqueous sodium hydroxide (24.9 ml) at room temperature for 11/2 hours and, after the addition of more ether (50 ml), the aqueous phase was separated, cooled (ice-H2O), stirred with fresh ether and acidified to Congo Red with N-aqueous hydrochloric acid. The ethereal solution of carboxylic acid was thrice washed with water, dried (MgSO4), and evaporated, to leave 1-(6-carboxyhexyl)-5-dibutoxymethylhydantoin (2.15 g) as a gum. When 1.89 g of the latter were cooled in ice-water and stirred with concentrated aqueous hydrochloric acid (8.5 ml), the resulting solution gave place spontaneously to a suspension of colourless crystals. The suspension was set at room temperature for 11/2 hours, diluted with water (10 ml) and set aside 15 minutes; the crystals were then collected, washed with water, dried in vacuo, suspended in ether (3 ml), and collected again, to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (0.74 g), m.p. 223.5°-225° C. (Found: C.51.86; H, 6.66; N, 10.62. C11H16N2O5 required, C, 51.56; H, 6.29; N, 10.93%). In dimethyl sulphoxide-d6, this compound exists predominantly as the masked aldehyde, 1-(6-carboxyhexyl)-5-hydroxymethyl- enehydantoin.
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(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:9]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nn(CCN3CCCCC3)cc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-Nitroindazole (1.00 g, 6.13 mmol) and and potassium carbonate (2.50 g, 18.1 mmol) in 20 mL of N,N-dimethylformamide was stirred for 30 minutes and then 1-(2-chloro-ethyl)-piperidine hydrochloride (1.74 g 9.45 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under vacuo and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 1.13–1.15 (m, 6H) 2.40 (m, 4H), 2.82 (t, 2H, J=6.44) 4.61 (t, 2H, J=6.44), 7.78 (m, 1H), 8.00 (m, 1H), 8.81 (s, 1H), 8.90 (d, 1H); MS (DCI/NH3) m/z 275 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:11][CH2:12][CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].C(=O)([O-])[O-:16].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]([OH:16])([CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(O)(C(=O)O)C(=O)OCC
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Air was bubbled for 1 hour at room temperature through a suspension of 15.0 g (72.7 mmol) diethylpropylmalonate and 47.6 g (145 mmol) cesium carbonate in 120 ml dimethylformamide. At 10-20° C. 150 ml water were added and stirring was continued at room temperature for 3 hours. Most of the dimethylformamide was then removed by vacuum distillation at 35° C. bath temperature. 1 l water was added and extraction with diethylether yielded 11.7 g 2-hydroxy-2-propyl-malonic acid monoethylester, MS (m/e): 189.1 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:11][C:12]([OH:14])=[O:13])(=[O:28])=[O:29]
Reactant: O=C(O)CC1NCCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.91 g of (1,2,3,4-tetrahydro-1-isoquinolyl)-acetic acid (Preparation 2.18) are suspended in 25 ml of dioxane, 10 ml of 1N NaOH are added, followed by portionwise addition of 2.3 g of 2-naphthalenesulphonyl chloride, and the mixture is maintained at pH=10.5-12 by addition of 1N NaOH. The mixture is kept stirring at a constant pH for 2 hours at RT. The reaction medium is diluted with 100 ml of water and is then washed twice with EtOAc and brought to pH=1.2 by addition of 6N HCl in the presence of EtOAc. This mixture is extracted with EtOAc, washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The expected product crystallizes from heptane, and is drained, washed with heptane and then dried to give 3.14 g, m.p.=132° C.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:16]1[CH2:17][NH:14][CH2:15]1
Reactant: Fc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cccc(OC2CNC2)c1
Yield: 67 %

Procedure:
A solution of 2.50 g of 1-benzhydryl-3-(3-fluoro-phenoxy)-azetidine in 10 mL of THF was added to a suspension of 10% Pd/C in methanol. Ammonium formate (4.6 g) were added portion wise and the reaction was heated under reflux for 3 h. The mixture was cooled, filtered through celite, and the filtrate was concentrated. The residue was triturated with CH2Cl2 and filtered. The filtrate was concentrated to give 0.840 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].C(O[CH2:18][CH3:19])C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:19]2[CH2:18][CH2:9]2)[CH:3]=1
Reactant: CCOCC
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(OC2CC2)c1
Temperature: 180 °C

Procedure:
A mixture of 3-bromophenol (2.4 g, 13.9 mmol), bomocyclopropane (6.66 ml, 83 mmol) and potassium carbonate (9.6 g, 69.5 mmol) in DMF (16 ml) was heated at 180° C. in a microwave oven for 8 hours. The reaction mixture was diluted with a mixture of diethylether and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and evaporated. An oil was obtained, 2.87 g, with a purity of 81%. This intermediate was used for the next reaction.
Reaction SMILES: [CH2:1]([N:3](C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)C.[C-:11]#[N:12].[Na+].O=O.C(=O)(O)[O-].[Na+].CO.[C:23](O)(=O)[CH3:24]>>[CH3:1][N:3]([CH:23]([CH3:24])[C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(C)c1ccccc1
Reactant: [C-]#N
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: O=O
Agent: [Na+]
Solvent: CO
Product: CC(C#N)N(C)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
N-ethyl-N-methylaniline (1 mmol), RuCl3-nH2O (0.05 mmol) and sodium cyanide (1.2 mmol) were charged into a 25-ml side-arm flask, the interior of the reacting container was replaced by oxygen, and an oxygen balloon was attached to supply oxygen at 1 atm. Then, 1.7 ml of a mixed solvent of methanol-acetic acid (volume ratio 3/1) was added thereto at room temperature. Reaction was effected by stirring the mixed liquid at 60° C. for 24 hours. After the reaction mixture liquid was made alkaline with the addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with 10 ml ethyl acetate once and with 5 ml ethyl acetate twice. The extracted liquid thus obtained was washed with saturated saline solution, and dried over sodium sulfate, thereby obtaining an ethyl acetate solution of N-phenyl-N-ethylaminoacetonitrile and 2-(N-methyl-N-phenylamino)propionitrile. This solution was analyzed by a gas chromatography internal standard method, which revealed the conversion rate of N-ethyl-N-methylaniline being 70% with a yield of N-phenyl-N-ethylaminoacetonitrile being 57% (vs. N-ethyl-N-methylaniline) and that of 2-(N-methyl-N-phenylamino)propionitrile being 7% (vs. N-ethyl-N-methylaniline).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](O)(=[O:11])[CH3:10].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: OCCCCCCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCCCCCCCl
Temperature: 10 °C

Procedure:
6-chlorohexanol (800 g) was added to anhydrous acetic acid (1,200 mL) cooled to 10° C. in an ice bath, and then pyridine (934 g) was dropped for 10 minutes. After the completion of dropping, they were refluxed for 2 hours. The reaction mixture was poured into water and toluene was further added and stirred. After neutralization the toluene layer with an aqueous saturated solution of sodium carbonate, it was washed with a small amount of water and further dried over anhydrous magnesium sulfate. Toluene and unreacted ingredients were distilled off from the toluene layer to obtain concentrates. The concentrates were purified by distillation under a reduced pressure to obtain 6-acetoxy chlorohexane (983 g). The boiling point was 82° C./5.3 hPa.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:17]#[CH:18])[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])[CH3:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:18]#[C:17][C:5]2[CH:6]=[C:7]3[C:12](=[C:3]([CH2:1][CH3:2])[CH:4]=2)[O:11][C:10]([CH3:13])([CH3:14])[CH2:9][C:8]3([CH3:16])[CH3:15])=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(CC)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure F and using 8-ethyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 48, 0.033 g, 0.136 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.034 g, 0.12 mmol), triethyl amine (2 mL), tetrahydrofuran (2 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) the title compound was obtained (0.035 g, 73%).