Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH:10]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[NH2:28]O.[NH4+].[OH-]>CC(O)=O.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:28]=[C:1]([CH3:2])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:21][CH:22]=1
Reactant: NO
Reactant: CCOC(=O)C(C(C)=O)C(CC(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Temperature: 25 °C

Procedure:
A mixture of α-acetyl-β-(4-fluorophenyl)-δ-oxobenzenepentanoic acid, ethyl ester (6.12 gm) and hydroxylamine hydrochloride (3.61 gm, 52 mmol) in glacial HOAc (83 ml) was refluxed for 1 hour. The reaction was cooled to room temperature and poured into an ice cold solution of concentrated NH4OH (115 ml) in H2O (300 ml). The resulting mixture was extracted twice with Et2O and the combined Et2O layers were washed with brine, dried (Na2SO4), filtered and stripped to yield a dark gummy residue. The residue was chromatographed (Flash, Merck SiO2, 8% EtOAc in hexane) to give 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethyl ester which was rechromatographed (8% EtOAc in hexane) to afford pyridine 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (1.652 gm, 24% from (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one) in >90% purity.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12].CCN(C(C)C)C(C)C.[Br:26][CH2:27][C:28](Br)=[O:29]>C1COCC1>[Br:26][CH2:27][C:28]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])=[O:29]
Reactant: O=C(Br)CBr
Reactant: Nc1sc2c(c1C(=O)NCCO)CCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Reaction time: 0.5 h
Yield: 43 %

Procedure:
2-Amino-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (4.6 g, 19.14 mmol) and DIPEA (4.95 g, 6.33 mL, 38.3 mmol) were dissolved in THF (100 mL) and the mixture purged with nitrogen and cooled in an ice bath. 2-Bromoacetyl bromide (3.86 g, 1.667 mL, 19.14 mmol) dissolved in THF (5 mL) was added dropwise and the reaction monitored by TLC. After 30 min TLC indicated 3:1 product: starting material with a faint spot for bis-acylated material. An additional quantity of 2-bromoacetyl bromide (0.97 g, 0.417 μL, 4.79 mmol) was added and stirring continued for a further 30 min. The mixture was quenched by addition of water before removal of THF under reduced pressure. The mixture was then partitioned between EtOAc/water and the organic layer collected—additional DCM was added to aid solubility. The aqueous layer was further washed with DCM. Combined organics were dried and concentrated to give a thick dark oil which was purified on silica eluting with 20-60% EtOAc/heptane. Desired fractions were collected and concentrated to yield the desired product as a light yellow solid (2.96 g, 8.23 mmol, 43%). The sample was used directly in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([N:26]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[C:5]([C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=3)=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Solvent: CCO
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)nn1-c1ccccc1
Yield: 71.5 %

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-methoxycarbonylpyridine (0.30 g, 1.09 mmoles), phenylhydrazine (0.27 ml, 2.72 mmoles) in ethanol (18 ml) was stirred at 100° C. for 72 hours. The solution was cooled and the solvent was removed. The residue was triturated with methanol to give a white solid, which was collected and air dried, yielding 0.26 g of 6-phenyl-8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one (71.5%), mp 144°-145° C.
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:35][CH:34]=2)=CC=1.[Br-].[Br-]>CO>[CH2:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([CH:32]=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)=[CH:38][CH:37]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: c1ccc([P+](Cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: CO
Product: CCCCCCCCCCCCCCCOc1ccc(C=Cc2ccc(C=Cc3ccc(OCCCCCCCCCCCCCCC)cc3)cc2)cc1
Yield: 92.9 %

Procedure:
In a 30 ml four-necked flask, 7.87 g (23.7 mM) of the p-pentadecanoxybenzaldehyde synthesized above and 8.65 g (11.0 mM) of p-xylylenebis(triphenylphosphonium bromide) were suspended in 100 ml of methanol, and 6.87 g (35.6 mM) of 28 wt % methylate was added dropwise at room temperature (25° C.). The resultant mixture was aged at a refluxing temperature of 65° C. for 3 hours. Methanol was removed by evaporation, and 200 ml of water was added to the residue, and the resultant was stirred. The precipitate formed was collected by filtration, washed with water and acetone, and dried to give 7.49 g of a 1,4-bis(4′-pentadecanoxystyryl)benzene isomeric mixture (compound (1a)). The 1H-NMR data for identification were as follows.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.S([O-])([O-])(=O)=[O:15].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11](=[O:13])[CH3:12])[CH2:1][CH2:2]1
Reactant: CC(=O)Nc1cccc2c1CCC2
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)CC2
Temperature: 0 °C

Procedure:
147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetone and combined with 770 μl of a 15% aqueous magnesium sulphate solution. The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassium permanganate are added batchwise. After 2 h the mixture is diluted with 50 ml of water, and extracted three times with 20 ml chloroform. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (85:15).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g) by alkylating tert-butyl (3RS,4RS)-4-(4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate; MS: 569 (M+H)+.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Br:24])[C:12]=1[O:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1>C(O)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Br:24])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17](=[O:3])[NH:16][N:15]=1
Reactant: CC(C)c1cc(Oc2c(Br)cc(CCC(=O)O)cc2Br)nnc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Br)cc(CCC(=O)O)cc2Br)n[nH]c1=O
Temperature: 120 °C
Yield: 72 %

Procedure:
A mixture of glacial acetic acid (16.7 mL), sodium acetate (480 mg, 5.85 mmol) and [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-proprionic acid (22) (800 mg, 1.67 mmol) was heated to 120° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was diluted with water (200 mL) and was made basic to pH=9 by the addition of a 1N aqueous sodium hydroxide solution. This solution was extracted with ethyl acetate (1×100 mL) and the ethyl acetate was discarded. The water layer was acidified to pH=3 by the addition of a 1N aqueous hydrochloric acid solution. The water layer was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated under vacuum. The resulting solid was slurried in ethyl acetate (20 mL). Heptane (20 mL) was added to this mixture. The solvents were then concentrated under vacuum to a volume of approximately 20 mL. The solids were filtered and washed with a 1:1 ethyl acetate:heptane solution (2×10 mL). The solid was dried under high vacuum to afford [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-proprionic acid (23) (553 mg, 72%) as an off-white solid; LRMS for C16H16Br2N2O4 (M+H) m/z=461. Molecular Weight=460.1249; Exact Mass=457.9477
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(=[O:12])=[O:11].C([N-]C(C)C)(C)C.[Li+].[CH:29]([Si:32]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[N:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C:35]([CH:42]=[O:43])=[CH:34]1)([CH3:31])[CH3:30].O>O1CCCC1>[F:1][C:2]1[C:7]([CH:42]([OH:43])[C:35]2[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[N:33]([Si:32]([CH:44]([CH3:46])[CH3:45])([CH:47]([CH3:49])[CH3:48])[CH:29]([CH3:30])[CH3:31])[CH:34]=2)=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1cccc(S(=O)(=O)Nc2ccc(F)cc2F)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)c(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncccc34)c2F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To N-(2,4-difluoro-phenyl)-3-methoxy-benzenesulfonamide (91, 0.148 g, 0.494 mmol) in tetrahydrofuran (10.0 mL) cooled in a −78° C. acetone/dry ice bath, under an atmosphere of nitrogen, was added lithium diisopropylamide (0.85 M in tetrahydrofuran, 1.45 mL, 1.23 mmol) dropwise. After 30 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (96, 0.15 g, 0.500 mmol, prepared as described in Example 12) was added in tetrahydrofuran (2.0 mL) into the reaction dropwise. Then the reaction was stirred for 1 hour at −78° C. and allowed to reach room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give light yellow solid (92, 0.080 g, 26.8%). MS(ESI) [M+H+]+=602.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.IC.[C:29]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:29][O:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(O)cnc23)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(OC)cnc23)C1
Yield: 30.5 %

Procedure:
To a solution of 1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one x149 (1.71 mmol, 1 eq, 0.6 g) in acetone (100 ml) is added iodomethane (17.1 mmol, 10 eq, 1.065 ml) and K2CO3 (17.1 mmol, 10 eq, 2.36 g). The mixture is refluxed for 5 minutes. Solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (AcOEt/hexane: 1/1) and recrystallized in AcOEt to afford 0.19 g of 1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 204.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][N:29]=[C:30]=[O:31]>ClCCl>[CH3:28][NH:29][C:30]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=3[Cl:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:31]
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 55 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 2 equiv. methylisocyanate would be added. The reaction would be shaken at room temperature overnight. The reaction would be concentrated in vacuo. The residue would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo would afford the title compound as hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[N+:22]([O-:24])=[O:23])[CH3:2].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
By using 448 mg of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine ethyl ester, 350 mg of imidazole and 2 ml of DMF, 331 mg (65%) of N-[4-benzyloxy-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: O=C(O)Cc1ccccc1OC(F)(F)F
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccccc3OC(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 2-(2-(trifluoromethoxy)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=1.88, min, m/z=484, 482
Reaction SMILES: [I-:1].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:7]=[C:8]([C@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[C:9]=1[F:10]>CC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:7]=[C:8]([C@H:11]([OH:24])[CH2:12][I:1])[C:9]=1[F:10]
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CI)c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Sodium iodide (3.34 g, 22.3 mmol) was added to a solution of ethyl 3-[3,4-difluoro-5-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl]propanoate (0.950 g, 2.22 mmol) in acetone (9.0 mL). The reaction mixture was heated at reflux for 18 h. The reaction was cooled to room temperature and concentrated. The residue was diluted with H2O and extracted two times with ethyl acetate. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Column chromatography (0-40% ethyl acetate:hexane) afforded 0.552 g (65%) of product: 1H NMR (400 MHz, chloroform-d) δ ppm 7.13 (d, J=5.81 Hz, 1 H) 7.01 (dd, J=10.61, 7.58 Hz, 1 H) 5.09 (dd, J=8.34, 3.54 Hz, 1 H) 4.15 (q, J=7.07 Hz, 2 H) 3.58 (dd, J=10.23, 3.16 Hz, 1 H) 3.41 (dd, J=10.36, 8.34 Hz, 1 H) 2.94 (t, J=7.58 Hz, 2 H) 2.62 (t, J=7.71 Hz, 2 H) 2.26 (s, 1 H) 1.26 (t, J=7.20 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: CNCCO
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)O)c2)c2ccc(Cl)cc2F)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 207, step 2, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 320, step 4) was coupled with 2-(methylamino)ethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=471.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])O[C:3]1([O:17]C)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][C:2]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:17]
Reactant: COC1(c2ccc(N3CCCCC3)cc2)OC1(C)C
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)c1ccc(N2CCCCC2)cc1)N1CCOCC1
Temperature: 130 °C

Procedure:
12.1 g (46.3 mmol) of 3,3-dimethyl-2-methoxy-2-(4-piperidinophenyl)-oxirane and 26.1 g (0.30 mol) of morpholine are added together, and the mixture is heated to the refluxing temperature (about 130° C.). After 6 hours the mixture is cooled down and the morpholine is dissolved off under reduced pressure. The residue is taken up in toluene and is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and concentrated. The residue is recrystallised from methanol. Melting point 159°-162° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CN(C)C=O.O>[CH2:14]([O:13][P:12]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reaction time: 1.5 h
Yield: 66 %

Procedure:
10 g (46.3 mmol) of 4-nitrobenzylbromide and 10.03 g (60.3 mmol) of triethyl phosphite are dissolved in 25 ml dimethylformamide. The reaction mixture is held at 155° C. for 1.5 h, diluted with 20 ml water and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated to yield 8.35 g (66%) of the crude title compound. MS: m/e=274.1 (M++H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:17](O)(=[O:20])[CH2:18][OH:19].O>C1C=CC=CC=1>[C:18]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:19])[CH2:17][OH:20]
Reactant: O=C(O)CO
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCOC(=O)CO

Procedure:
To 101 g (1.5 moles) of butyl alcohol containing 5 g of ρ-toluene sulfonic acid in 325 ml of benzene at reflux was added dropwise 150 g (ca. 1.5 moles acid) of 70% glycolic acid. The flask was equipped with a Dean-Stark trap to collect the 30% of water from the aqueous glycolic acid mixture and to collect the 27 g (1.5 moles) of water liberated during the reaction--a total of ca. 68 ml. The benzene solution of the product was water washed and dried over anhydrous sodium sulfate. The benzene was stripped off on a rotary evaporator. A short pass distillation at reduced pressure produced a good grade butyl glycolate. The structure was established by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2)[CH:2]=[CH2:3].F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[C:14]([CH3:19])=[CH:13]2)[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCOc1ccc2[nH]c(C)cc2c1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: C=CCN(C)CCCCOc1ccc2c(c1)cc(C)n2-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 9.1, Allyl-methyl-[4-(2-methyl-1H-indol-5-yloxy)-butyl]-amine and 1-Fluoro-4-trifluoromethyl-benzene were converted to yield Allyl-methyl-{4-[2-methyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yloxy]-butyl}-amine as yellow viscous oil, MS: 417 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[CH3:5][C:6]1[C:7](=O)[O:8][C:9](=[O:12])[C:10]=1[CH3:11]>O>[CH3:5][C:6]1[C:7](=[O:8])[NH:3][NH:4][C:9](=[O:12])[C:10]=1[CH3:11]
Reactant: NN
Reactant: CC1=C(C)C(=O)OC1=O
Agent: Cl
Solvent: O
Product: Cc1c(C)c(=O)[nH][nH]c1=O
Temperature: 100 °C
Yield: 62.5 %

Procedure:
Hydrazine dihydrochloride (83.6 g) was dissolved in water (20 ml), heated to 100° C., and 3,4-dimethylfuran-2,5-dione (100.4 g) was introduced while stirring. Then the mixture was heated to reflux for 3 h. Subsequently, the precipitate formed was filtered off with suction, washed with water and dried. The residue was suspended in EA (2 l), filtered off with suction, and was dried. 69.7 g of the title compound were obtained. LC-MS rt: 0.19 min [M+H]+: 141.1 (met. b)