Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[C:6]([F:9])[N:7]=[CH:8][C:3]=2[CH2:2][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:11][CH:12]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(CBr)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)cc2-c2ccc(Cl)cc2)CC1

Procedure:
A mixture of EXAMPLE 307B (1.24 g), tert-butyl piperazine-1-carboxylate (0.768 g), and potassium carbonate (0.570) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel using 10% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:14])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3ccc(C#N)cc3[nH]2)CC1

Procedure:
In the same manner as in Example 1 (2), 6-cyano-2-indolecarboxylic acid (244 mg, 1.31mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (300 mg, 1.3 mmol ) were condensed. The reaction mixture was purified by silica gel column chromatography (chloroform/methanol=50/1-1/1) to give 465 mg of t-butyl trans-[4-[(6-cyano-2-indolyl)carbonylamino]cyclohexyloxy]acetate as a brown solid (89%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][CH:21]1[O:25][CH:24]([CH3:26])[CH:23]([CH3:27])[O:22]1>>[CH3:27][CH:23]1[CH:24]([CH3:26])[O:25][CH:21]([CH2:20][NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[O:22]1
Reactant: CCCCOc1ccccc1N
Reactant: CC1OC(CBr)OC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCOc1ccccc1NCC1OC(C)C(C)O1
Temperature: 100 °C

Procedure:
2-n-Butoxyaniline (99 grams; 0.6 moles) and sodium carbonate (31.6 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (25 ml) was added and the reaction mixture was heated at a temperature of about 100° C. for a period of about 4 hours. After this time the reaction mixture was filtered and additional sodium carbonate (5.0 grams) was added to the filtrate. The mixture was then vacuum distilled and the fraction boiling at 123° C. and 0.05 mm of Hg pressure was collected to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-n-butoxyaniline.
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.CC1C=CC([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=C(C=1)C(O)=O>>[CH3:28][C:25]1[CH:26]=[CH:27][C:3]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:4]([CH:24]=1)[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6]
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2ccnn2)c(C(=O)O)c1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: Cc1ccc(-n2ccnn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid (CAS number 1149352-55-5; 65 mg, 0.32 mmol) to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:42][C@@H:43]([CH3:59])[CH2:44][N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[C:52]([Cl:58])[CH:51]=2)=[N:46]1>C(Cl)Cl>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:42][C@@H:43]([CH3:59])[CH2:44][N:45]2[CH:49]=[CH:48][C:47]([C:50]3[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[C:52]([Cl:58])[CH:51]=3)=[N:46]2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (0.59 g; 3.84 mmol) and DIPEA (1.0 ml; 5.75 mmol) were dissolved in 4 ml of dry DCM. Anhydrous HOBt (0.78 g; 5.75 mmol) and EDCI (1.10 g; 5.75 mmol) were added at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g; 3.84 mmol) was dissolved in 4 ml of DCM and the reaction was stirred for overnight at RT. 40 ml of DCM was added and organic layer washed with 3×15 ml of water. Combined water phases were washed with 2×20 ml of DCM. Both organic phases were dried over Na2SO4, filtered and evaporated to dryness. Both crude product fractions were combined and purified by CombiFlash (2% MeOH in DCM). Product fractions were combined and evaporated to give 497 mg of product. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H, J=6.7 Hz), 2.49 (s, 3H), 4.31 (m, 2H), 4.46 (sept, 1H, J=6.7 Hz), 6.93 (d, 1H, J=2.4 Hz), 7.31 (s, 1H), 7.81 (d, 1H, J=2.4 Hz), 7.92 (d, 1H, J=7.9 Hz), 7.97 (d, 1H, J=8.1 Hz), 8.03 (d, 1H, J=1.3 Hz), 8.48 (d, 1H, J=8.5 Hz), 14.16 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:16]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc(Oc2ccccc2)c1
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
The invention relates to a process for the oxidation of meta-phenoxytoluene by selenium dioxide in the presence of a dehydrating agent to produce meta-phenoxybenzaldehyde containing less than 250 ppm dissolved selenium. The invention relates to a process whereby the benzaldehyde can be recovered from the reaction mixture as the bisulfite addition product at the rate of 90%/hr. The invention further relates to a stoichiometric selenium dioxide oxidation of meta-phenoxytoluene to yield a selectivity of about 90% or greater based on the toluene.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[F:48][C:49]([F:53])([F:52])[CH:50]=O>CN(C=O)C.C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:50]([C:49]([F:53])([F:52])[F:48])=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Reactant: O=CC(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF was combined with 30 mg (0.26 mmol) trifluoroacetaldehyde and 3 drops of TFA and stirred for 2 h at 100° C. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]([CH3:21])([CH3:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][S:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:21])[CH3:20])(=[O:17])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 4-(2-methanesulfonylethyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (510 mg, 1.59 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white solid (320 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.49 (s, 1 H); 3.12-3.03 (m, 5 H); 2.92-2.84 (m, 4 H); 2.60 (s, 2 H); 2.53-2.47 (m, 2 H); 1.06 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1.[C:24](Cl)(=[O:29])[CH2:25][C:26](Cl)=[O:27].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1COCC1>[C:19]([O:18][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[NH:1][C:26](=[O:27])[CH2:25][C:24]2=[O:29])=[CH:11][CH:12]=1)=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cc1cccc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(NC(=O)OC(C)(C)C)cc1
Yield: 33.3 %

Procedure:
tert-Butyl 4-(2-amino-3-methylphenylamino)phenylcarbamate (294 mg, 0.938 m mmol) was dissolved in THF (30 mL), and then the solution was added dropwise with malonyl chloride (91 μL, 0.938 mmol) under ice cooling. After the disappearance of the starting materials was confirmed, the reaction mixture was added with aqueous sodium hydrogencarbonate, and ethyl acetate, and the organic layer was separated. The organic layer was washed with brine and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=100/1) to obtain the title compound (119 mg, yield 33%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:26][CH2:27][CH3:28]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH3:28]
Reactant: CCCI
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Product: CCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 97.3 %

Procedure:
In a similar manner to Example 10(b), by reaction of 2 g (6.2 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) benzaldehyde [prepared in Example 16(a)] with 670 μl (6.8 mmol) of 1-iodopropane, 2.2 g (88%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.N1C=CC=CC=1.[Br:16]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:16][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1
Reactant: CN1CCCC(CO)C1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CN1CCCC(CBr)C1
Temperature: 0 °C
Reaction time: 94 h
Yield: 105.1 %

Procedure:
3-(Hydroxymethyl)-1-methylpiperidine (2 g, 15.5 mmoles) was dissolved in anhydrous acetonitrile (32 mL) and anhydrous pyridine (2.02 mL, 24.8 mmoles) was added and the solution was cooled to 0° C. Dibromotriphenylphosphorane (8.49 g, 20.2 mmoles) was added at 0° C. and the mixture was allowed to warm up to 25° C. and was stirred for 94 h. The mixture was evaporated to dryness and the residue was chromatographed on a silica gel column (30×5 cm) using gradient elution with dichloromethane, 35% diethyl ether in dichloromethane and 5-10% methanol in dichloromethane as the eluant to give 3-(bromomethyl)-1-methylpiperidine (3.13 g, 100%): FABMS: m/z 192.1 (MH+); δH (CDCl3) 1.52 (1H, m, CH2), 1.99 (2H, m, CH2), 2.43 (1H, m, CH2), 2.75 (2H, m, CH2), 2.82 (1H, m, CH), 2.86/2.88 (3H, s, NCH3), 3.42/3.49 (2H, dd, —CH2Br) and 3.56 ppm (2H, m, CH2); δC (CDCl3) CH3: 44.3; CH2: 22.1, 26.6, 35.4, 54.8, 58.2; CH: 34.6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2)CC1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)C1(c2ccc(S(=O)(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Chlorosulfonic acid (10 mL) was cooled to 0° C. Then compound 36A (6.80 g, 38.6 mmol) was added over 30 min. The mixture was stirred at RT for 3 h and was poured into ice (˜500 g). The cloudy solution was extracted with ether (2×200 mL). The extracts were dried with magnesium sulfate and concentrated to give a brown oil which was passed through a short pad of silica gel to afford the desired product 36B (6.05 g, 57%) as white plates. MS: 239 (M−Cl)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11].C[O:13][C:14](=[O:17])[CH:15]=[CH2:16]>CO.C(OCC)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:16][CH2:15][C:14]([OH:17])=[O:13]
Reactant: C=CC(=O)OC
Reactant: COc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccccc1SCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
1.5 ml of a solution of 1N sodium hydroxide in methanol are added to a solution of 20.2 g of 2-methoxybenzenethiol in 20 ml of methanol and 20 ml of diethyl ether followed by cooling to 0° C. 13.9 ml of methylacrylate was then dropwise added to this solution. After completion of dropping, the reaction mixture was warmed to room temperature and stirred overnight. After concentrating the reaction mixture by a rotary evaporator, 8.7 g of sodium hydroxide, 100 ml of water and 35 ml of methanol was added followed by stirring vigorously overnight. The reaction mixture was acidified with concentrated hydrochloric acid while cooling and the resulting solution was extracted with chloroform. The chloroform layer was dried with magnesium sulfate, the solvent was distilled off and the resulting crystal was recrystallized from chloroform-hexane to obtain 25.4 g of the target 2-(2-methoxyphenylthio) ethanecarboxylic acid (yield: 83%, m.p.: 91°-91.5° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11](O)[CH2:10]2)=[C:4]([F:15])[CH:3]=1.S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([Cl:18])[CH2:10]2)=[CH:6][C:7]=1[F:8]
Reactant: OC1CCC(c2cc(F)c(Br)cc2F)C1
Reactant: O=S(Cl)Cl
Product: Fc1cc(C2CCC(Cl)C2)c(F)cc1Br

Procedure:
A solution of 27.7 g (0.1 mol) of 3-(4-bromo-2,5-difluorophenyl)cyclopentanol in 150 ml of thionyl chloride was heated at reflux until gas evolution ceased (4 hours). The solvent was removed in vacuo and the residue was triturated with toluene (2×200 ml) which was also removed in vacuo. The residue was dissolved in ether, washed with water (3×100 ml), dried (MgSO4), filtered, and evaporated in vacuo to give 26.2 g of the title compound which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[I:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[S:16]>C(O)C>[I:11][C:12]1[CH:13]=[C:14]([C:15]2[S:16][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[N:17]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)c1cccc(I)c1
Solvent: CCO
Product: Ic1cccc(-c2nc(-c3ccccn3)cs2)c1
Yield: 41.5 %

Procedure:
A solution of 2-bromoacetylpyridine (400 mg, 2.0 mmol) in ethanol (5 mL) was treated with 3-iodothiobenzamide (1.2g, 6 mmol) and the mixture heated at reflux for 16 hours. After cooling the mixture was concentrated in vacuo. Silica gel chromatography of the residue using a gradient of hexane to ethyl acetate afforded 302 mg (55%) of 2-(3-iodophenyl)-4-(pyridin-2-yl)-1,3-thiazole, as a white solid.
Reaction SMILES: C(OC1CC2C3[C:15](=CC=CC=3)[NH:14][C:13]=2CC1)(=O)C1C=CC=CC=1.[H-].[Na+].ClC1C=CC(CCl)=CC=1.C(O[CH:43]1[CH2:55][C:54]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=3)[C:46]=2[CH2:45][CH2:44]1)(=O)C1C=CC=CC=1>O.CN(C)C=O>[Cl:63][C:60]1[CH:61]=[CH:62][C:57]([CH2:56][N:47]2[C:46]3[CH2:45][CH2:44][CH:43]([N:14]([CH3:15])[CH3:13])[CH2:55][C:54]=3[C:53]3[C:48]2=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:58][CH:59]=1
Reactant: O=C(OC1CCc2c(c3ccccc3n2Cc2ccc(Cl)cc2)C1)c1ccccc1
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Agent: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCc2c(c3ccccc3n2Cc2ccc(Cl)cc2)C1

Procedure:
A mixture of 29.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 4.3 g. of sodium hydride (56% in mineral oil) in 200 ml. of dimethylformamide was heated on a steam bath and 16.1 g. of p-chlorobenzyl chloride in 30 ml. of dimethylformamide was added dropwise. The reaction mixture was heated two hours, cooled, and diluted with water. The resulting oil was washed with water and crystallized from isopropyl alcohol to give 12.7 g. of 3-benzoyloxy-9-(p-chlorobenzyl)-1,2,3,4-tetrahydrocarbazole, m.p. 150°-152° C.
Reaction SMILES: [I:1]I.[CH3:3][C@@H:4]1[C@@:21]2([CH3:22])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:23])=[CH:7][C:6](=[O:24])[CH2:5]1>C(O)(=O)C>[I:1][CH:5]1[C@H:4]([CH3:3])[C@@:21]2([CH3:22])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:23])=[CH:7][C:6]1=[O:24]
Reactant: II
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Solvent: CC(=O)O
Product: C[C@H]1C(I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Yield: 106.6 %

Procedure:
10.3 g (40 mmol) of iodine is added to 10 g (33 mmol) of 1α-methyl-androst-4-ene-3,17-dione and 7.33 g (40 mmol) of CuO in 300 ml of glacial acetic acid with stirring at room temperature. It is stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, acetic acid is distilled off. The residue is added in 600 ml of water, the product is extracted 3 times with 200 ml of ethyl acetate each, the combined ethyl acetate phases are washed neutral with sodium thiosulfate solution, then with saturated sodium carbonate solution and dried on sodium sulfate. After concentration by evaporation of the solution and drying of the substance at 0.8 torr, 15.0 g (106% of theory) of 2-iodo-1α-methyl-androst-4-ene-3,17-dione is obtained as crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[N:51]1([CH2:57][C:58]([N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)=[O:59])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:54]3[CH2:53][CH2:52][N:51]([CH2:57][C:58](=[O:59])[N:60]4[CH2:61][CH2:62][CH2:63][CH2:64]4)[CH2:56][CH2:55]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1)N1CCCC1
Yield: 58.9 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.14 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.25 mL, 2.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (305 mg, 1.59 mmol), 1-hydroxybenzotriazole monohydrate (200 mg, 1.48 mmol) and 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (337 mg, 1.71 mmol) in a similar manner to Step 7 of example 1, was triturated in mixed solvent of ethyl acetate/methanol to obtain Compound 121 (298 mg, 60%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:37])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.C(C(CCCC)[CH2:41][O:42]C(Cl)=O)C.N1C=CC=CC=1>CN(C=O)C>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]3[NH:37][C:41](=[O:42])[O:1][N:2]=3)=[CH:11][CH:10]=2)/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC/C(=C(/c1ccc(/C=C/C(N)=N/O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC/C(=C(/c1ccc(/C=C/c2noc(=O)[nH]2)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a solution of (1Z,2E)-N′-hydroxy-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylimidamide (51 mg, 0.1 mmol) in anhydrous DMF (0.4 mL) was added 2-ethylhexylchloroformate (20 μL, 0.1 mmol) followed by pyridine (9 μL, 0.11 mmol). The reaction mixture was stirred at 0° C. for 1 h and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organics were dried over MgSO4 and concentrated. The residue was dissolved in xylenes (1 mL), heated at 130° C. for 2 h, and then concentrated to afford 25 mg of the title compound. LCMS: 519 (M+H)+.
Reaction SMILES: Cl[C:2](OCC1C=CC=CC=1)=[O:3].[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([NH2:33])([CH2:31][OH:32])[CH2:29][OH:30])=[CH:24][CH:25]=1.Cl.Cl>[OH-].[Na+]>[OH:32][CH2:31][C:28]1([CH2:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])=[CH:25][CH:24]=2)[CH2:29][O:30][C:2](=[O:3])[NH:33]1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCc1ccc(CCC2(CO)COC(=O)N2)cc1

Procedure:
Benzyl chloroformate (0.45 ml; 3.2 mmol) is added to a suspension of FTY720.HCl (1.03 g, 3 mmol) in 2N NaOH (20 ml). The reaction is kept at RT over night and in order to complete the reaction further benzyl chloroformate (0.9 ml; 6.4 mmol) is added. After 2 days at RT the reaction is acidified with 1N HCl, extracted with methylenechloride and purified on a silica gel column using methylenechloride/methanol/acetic acid50% (9/1/0.125) as mobile phase.