Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[N:20]([CH2:34][CH3:35])[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH:23]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH2:34]([N:20]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=2)=[CH:23][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)=[N:21]1)[CH3:35]
Reactant: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as yellow crystals.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1)(=O)[NH2:2].O=P(Cl)(Cl)Cl.O>CN(C=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(CCc1ccccc1)n1cnc(C(N)=O)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)n1cnc(C#N)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
A solution of ethyl 2-(4-carbamoyl-1-imidazolyl)-4-phenyl-butyrate (obtained in Preparation 2) in DMF (5 ml) was added to an ice-cooled solution of POCl3 (0.71 ml) in DMF (6 ml) under nitrogen atmosphere. After 1.5 h, the solvent was poured into water (50 ml) and the solution was neutralized with saturated NaHCO3aq. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel (16 g) column chromatography eluting with chloroform/methanol (100:1) to give ethyl 2-(4-cyano-1-imidazolyl)-4-phenylbutyrate (435 mg, 101.2%).
Reaction SMILES: [Cl-].C([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15](=[O:36])[CH2:16]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[CH:47]=O.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1/[CH:47]=[CH:16]/[C:15]([N:10]1[CH2:9][CH2:13][O:12][C:11]1=[O:14])=[O:36]
Reactant: O=C(C[PH](c1ccccc1)(c1ccccc1)c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCOC1=O
Yield: 69.8 %

Procedure:
A mixture of (4S)-4-benzyl-3-[(triphenylphosphino) acetyl]-1,3-oxazolidin-one chloride (10 mg, 0.193 mmol), 2-naphthaldehyde (30 mg, 0.193 mmol), triethylamine (0.030 ml, 0.212 mmol) and 4-(dimethylamino)pyridine in acetonitrile (5 ml) was heated under reflux for 24 h. After evaporation, the residue was dissolved in hexaneetherdichloromethane and chromatographed on flash silica eluting with hexane:ether 3:2 to give a white solid (36 mg, 52%) of 3-[(E)-3-Naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one. M/e 358 (MH+).
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:5]([O:7]CC)=[O:6])=[O:2].[OH-].[Na+].Cl>C(O)C>[CH:1]([NH:3][CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:5]([OH:7])=[O:6])=[O:2]
Reactant: CCOC(=O)C(NC=O)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=CNC(C(=O)O)C1CCOCC1

Procedure:
To a solution of ethyl (formylamino)(tetrahydro-2H-pyran-4-yl)acetate (M. J. Burk et al., J. Am. Chem. Soc., 117, 9375-9376 (1995); 0.30 g) in ethanol (7 ml) was added a 1 N aqueous sodium hydroxide solution (2.8 ml), and mixed at 80° C. for 40 minutes. The reaction mixture was neutralized by adding 1 N hydrochloric acid, and then water was removed by azeotropy with toluene to obtain (formylamino)(tetrahydro-2H-pyran-4-yl)acetic acid as a crude product. In the same manner as in Example 50a), 2-(4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperazinyl)-2-oxo-1-tetrahydro-2H-pyran-4-ylethylformamide was obtained from this carboxylic acid as a crude product. The product was dissolved in methanol (7 ml) and diethyl ether(14 ml). A 4 N solution of hydrogen chloride in ethyl acetate (3.5 ml) was added and mixed at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (14 ml), triethylamine (0.39 ml) and 4-chlorophenyl isocyanate (0.21 g) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound as colorless powder (0.03 g, 5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16]1([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:23][CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(C3CCCCC3)cc2)c1C(=O)OC
Yield: 78 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-cyclohexylaniline (0.54 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.90 g of the product at 90:10 hexanes-ethyl acetate, in 78% yield: 1H NMR (CDCl3) δ 1.27-1.44 (m, 6H), 1.73-1.85 (m, 4H), 2.45-2.55 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 7.00-7.10 (m, 3H), 7.15-7.18 (m, 2H), 7.23-7.34 (m, 2H), 8.07 (br, 1H).
Reaction SMILES: C([O:4][CH:5]([CH3:44])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][C@@H:34]2[C@@H:42]3[C@@H:37]([NH:38][C:39]([NH:41]3)=[O:40])[CH2:36][S:35]2)[C:11]1=[O:12])(=O)C.N>CO.Cl>[C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:13]1[C:14]2[N:15]=[CH:16][N:17]([CH3:21])[C:18]=2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:44])[C:11]1=[O:12])(=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]1[C@@H:42]2[C@@H:37]([NH:38][C:39]([NH:41]2)=[O:40])[CH2:36][S:35]1
Reactant: CC(=O)OC(C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)CCCC[C@H]2SC[C@@H]3NC(=O)N[C@@H]32)c1=O
Agent: Cl
Agent: N
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.3 %

Procedure:
A solution of (R)-1-(5-acetoxyhexyl)-3-(N-biotinyl-6-aminohexyl)-7-methylxanthine (110 mg) in methanol (10 ml) was treated with one drop of concentrated hydrochloric acid solution. After stirring al room temperature for 14 hours, the mixture was treated with 2M solution of ammonia in methanol (3 ml) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20methano/dichloromethane to provide (R)-3-(N-biotinyl-6-aminohexyl)-1-(5-hydroxyhexyl)-7-methylxanthine (CT12460) (66 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14].O>O1CCCC1.[Cu]Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([CH3:15])([CH3:10])[CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)=CC=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cu]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 21.6 grams (0.10 mole) of 4-chlorophenylmagnesium bromide (1M in diethyl ether) in 100 mL of tetrahydrofuran is cooled to -15° C., and 0.7 grams (catalyst) of copper(I) bromide is added in one portion. Upon completion of addition, 9.7 mL (0.10 mole) of 3-methyl-2-butenal is added dropwise during a 1.5 hour period, while maintaining the reaction mixture temperature below -10° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature, where it is stirred for about 18 hours. The reaction mixture is then poured into 300 mL of water and extracted with two 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 50% petroleum ether in methylene chloride as the eluant. The appropriate product-containing fractions are combined and concentrated under reduced pressure, yielding 7.6 grams of 3-(4-chlorophenyl)-3-methylbutyraldehyde. The NMR spectrum is consistent with the proposed structure. The reaction is repeated.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:9][CH:10]([CH2:22][CH3:23])[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])([C:13]#[N:14])[CH:12]=1)=[O:7])C.Cl>C(O)C>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1([C:13]#[N:14])[CH:10]([CH2:22][CH3:23])[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12]1
Reactant: CCOC(=O)C1=CC(C#N)(c2ccccc2Br)C(CC)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1SC(C(=O)O)=CC1(C#N)c1ccccc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Add ethanol (50 ml) and 1M aqueous solution of NaOH to 3-(4-(bromophenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid ethyl ester (5.0 g, 13.73 mmol) and stir at 60° C. for 1h. Cool down and acidify with 3M HCl until white solid precipitates. Filter and wash solid with water and hexanes successively. Dry overnight to give 4.34 g as a white solid. Mass spectrum ESI positive (m/z): 366 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O-])=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[Li+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:36]2[CH:37]=[CH:38][CH:39]=C[C:35]=2[N:34]=[N:33]1.NN1CCCCC1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([C:13]([NH:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C([O-])C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NN1CCCCC1)C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Part B: A mixture of the crude lithium 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (1.0 gram, ˜0.0027 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophos-phate (BOP) (1.2 gram, 0.0027 mol), 1-aminopiperidine (0.3 gram, 0.003 mol) and triethylamine (1 ml) in DMF (30 ml) is stirred at room temperature for 16 hours. After concentration in vacuo, water is added and the resulting mixture is extracted (2×) with dichloromethane. The dichloromethane layers are collected, dried over MgSO4, filtered and concentrated in vacuo to give a residue that is further purified by flash chromatography (silicagel, dichloromethane/methanol=95/5 (v/v)) to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)—N—(piperidin-1-yl)-4,5-dihydro-1H-imidazole-4-carboxamide (380 mg, 31% yield). Melting point: 113–116° C. 1H-NMR (200 MHz, CDCl3): δ 1.33–1.48 (m, 2H), 1.60–1.80 (m, 4H), 2.68–2.82 (m, 4H), 4.28–4.35 (m, 2H), 4.84 (dd, J=11 and 9 Hz, 1H), 6.65 (br d, J=8 Hz, 2H), 7.11 (br d, J=8 Hz, 2H), 7.23–7.33 (m, 2H), 7.41 (d, J=2 Hz, 1H), 7.57 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccncc1I
Reactant: COc1ccc2c(c1)C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Yield: 56.2 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-35b: 1 g, 5.64 mmol) was reacted with 3-iodo-4-methyl-pyridine (1.237 g, 5.64 mmol), 1,4-dioxane (300 mL), copper iodide (107.4 mg, 0.564 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (240.2 mg, 1.69 mmol) and potassium phosphate (2.98 g, 141 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 850 mg of the product (56% yield).
Reaction SMILES: [ClH:1].[CH2:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>N1C=CC=CC=1>[CH2:2]([Cl:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCO
Reactant: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCl

Procedure:
In JP 74/034 646, for example, n-octyl alcohol is reacted with HCl gas at 130° C., with pyridine as a catalyst, to form n-octyl chloride. The product is distilled off at reduced pressure. The yield here is only 93.6%, based on the alcohol used.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH:35]N)=[CH:27][CH:26]=1>>[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:27][CH:26]=1
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=434.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]([O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][N:10]=1)([CH3:6])[C:3]([OH:5])=[O:4].[H-].[Na+].Cl[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.Cl.[OH-].[Na+]>CN(C=O)C.C(O)C.O>[CH3:6][C:2]([O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH:29]2[C:30]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26][CH2:27][CH2:28]2)[N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(OCc1n[nH]c2ccccc12)C(=O)O
Reactant: ClC1CCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(OCc1nn(C2CCCc3ccccc32)c2ccccc12)C(=O)O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
To a solution of 2-methyl-2-[(1H-indazol-3-yl)methoxy]propanoic acid (26 g; 0.093 mol) in DMF (200 ml) was added 60% NaH (10 g; 0.25 mol) and the mixture was stirred for 10 minutes at 60° C. 1-chloro-1,2,3,4-tetrahydronaphthalene (0.217 mol) was then added to the mixture and the whole was stirred at 60° C. for 18 hours. The reaction was stopped by pouring the mixture into water (1 L), followed by acidifying with 5 N HCl and extracting the product with diethyl ether (3×250 ml). The residue obtained was dissolved in 95° ethanol (100 ml) and treated at reflux with 1N NaOH (200 ml) for 2 hours. The solution was then cooled to room temperature and washed with diethyl ether (3×200 ml). The alkaline phase was then acidified with concentrated HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were concentrated under reduced pressure and the crude residue obtained was purified by crystallization from ethyl acetate. 31 g of 2-methyl-2-{[1-(1,2,3,4-tetrahydronaphth-1-yl)-1H-indazol-3-yl]methoxy}-propanoic acid were thus obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH3:26]>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH3:26])(=[O:5])=[O:4]
Reactant: COc1cc(C#N)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 ml (141 mmol) of trifluoromethanesulfonic anhydride are slowly added dropwise to a solution of 20 g (134 mmol) of 4-hydroxy-3-methoxybenzonitrile in pyridine (80 ml), keeping the reaction temperature below 25° C. with the aid of an ice bath. The suspension is then stirred at RT for 1 h. Ice-water (400 ml) is added, and the suspension is stirred further until room temperature is reached. It is then filtered, the solid is dissolved in ethyl acetate, and the solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. 37.13 g (92% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Br[CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:22][CH2:21][CH2:20][CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:12][CH:13]=1
Reactant: Cc1cc2ccccc2n1-c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cc2ccccc2n1-c1ccc(OCCCCl)cc1
Yield: 56 %

Procedure:
4-(2-Methylindol-1-yl)phenol (0.36 mmol) was heated at 70° C. in 2-butanone (3 mL) with 1-bromo-3-chloropropane (0.107 mL, 1.08 mmol) and potassium carbonate (0.15 g, 1.08 mmol) overnight. The solvent was evaporated. The resulting residue was diluted with ethyl acetate and washed with saturated ammonium chloride solution. The aqueous layer was back-extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave the desired product as a colorless oil, 60 mg (56% yield, 2 steps). LC-MS (C18H18ClNO calc'd 299) m/z 300, 302 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])=[C:7]([CH3:18])[C:6]=2[CH:19]=1.[BH4-].[Na+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[OH:11])=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
(5-Bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanone (7.5 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (100 mL) and methanol (15 mL), and sodium borohydride (90%, 1.9 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (10 mL) and 1N hydrochloric acid (50 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (7.4 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.C([Li])CCCCC.CCCCCC.[Cl:23][CH2:24][C:25]([CH2:27][Cl:28])=[O:26]>C(OCC)C>[Cl:23][CH2:24][C:25]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1)([OH:26])[CH2:27][Cl:28]
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: O=C(CCl)CCl
Agent: [Li]CCCCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(CCl)(CCl)c1cc(F)cc(Cl)c1

Procedure:
Preparation according to Preparation 1: 1-bromo-3-chloro-5-fluorobenzene (5 g, 23.9 mmol), dry diethyl ether (100 mL), n-hexyllithium in hexane (2.3 M, 10.4 ml, 23.9 mmol) and 1,3-dichloroacetone (3.03 g, 23.9 mol). Yield: 4.49 g (73%). MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 209 (65), 207 (bp), 211 (11), 143 (28).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:13])[CH3:12])=[CH:2]1.O1CCOCC1.C(N(C(C)C)CC)(C)C.[F:29][C:30]([CH3:41])([CH3:40])[CH2:31]OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:13][CH2:31][C:30]([F:29])([CH3:41])[CH3:40])[CH3:12])=[CH:2]1
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Temperature: 75 °C
Reaction time: 24 h

Procedure:
(2R)-1-(1H-indol-3-yl)propan-2-amine (3.81 kg, 21.21 moles) was added to a 100 L glass lined jacketed vessel under an atmosphere of nitrogen. 1,4-dioxane (23 L) was added, and the agitator was switched on. Diisopropylethylamine (5.55 L 31.82 moles) was added to the stirred suspension followed by (2-fluoro-2-methyl-propyl)trifluoromethanesulfonate (5.55 kg, 23.77 moles). 1,4-Dioxane (4 L) was added to the vessel, and the mixture was heated to 75° C. Heating was continued for 24 hours before cooling the mixture to 25°C. Water (30.5 L) was added to the vessel, followed by toluene (30.5 L). After 40 minutes the agitator was switched off and the layers were allowed to separate. The aqueous layer was removed and water (30.5 L) was added to the organic solution. The mixture was agitated for 15 minutes before allowing the layers to separate. The aqueous layer was removed from the vessel. The organic solution was concentrated by vacuum distillation (jacket temperature 65° C., 110 mbar pressure) until approximately 27 L of distillate had been removed. The remaining solution in the vessel was cooled to afford (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine as a solution in toluene (33% w/w) (15.4 Kg, 97%). 1H NMR (500 MHz, DMSO, 27° C.) 0.98 (3H, d), 1.26 (3H, d), 1.30 (3H, d), 2.57-2.75 (3H, m, 2.81 (1H, dd), 2.84-2.92 (1H, m), 6.97 (1H, t), 7.06 (1H, t), 7.11-7.22 (1H, multiplet obscured by toluene signals), 7.34 (1H, d), 7.52 (1H, d), 10.80 (1H, s).