Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[C:31]([NH2:39])(=[NH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][N:39]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:38]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: N=C(N)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (100 mg, 0.35 mmol), diisopropylethylamine (186 μL, 1.05 mmol) and benzamidine hydrochloride (55 mg, 0.35 mmol) in DMF (2 mL) was stirred at rt for 18 h. Diethylazodicarboxylate (110 μL, 0.7 mmol) was added and mixture was stirred for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound (110 mg, TFA salt) as a white solid. (M+H)+=403. 1H NMR (400 MHz, DMSO d6) δ ppm 1.31 (s, 9H), 6.94 (dd, J=7.83, 1.26 Hz, 1H), 7.16 (dd, J=7.58, 1.26 Hz, 1H), 7.20-7.27 (m, 2H), 7.44 (dd, J=8.09, 1.77, 1H), 7.48-7.56 (m, 3H), 7.79 (dd, J=4.80, 1.51 Hz, 1H), 8.20 (dd, J=7.83, 1.52 Hz, 2H), 9.04 (dd, J=7.83, 1.52 Hz, 1H), 10.93 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Reactant: BrCC1CC1
Product: CC(=O)NC(C)c1cc2cc(CCc3ccc(OCC4CC4)cc3)ccc2o1
Yield: 32 %

Procedure:
Using N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (328 mg, 1.01 mmol) obtained in Example 157 and (bromomethyl)cyclopropane (3.97 g, 29.3 mmol) and in the same manner as in Example 158, the title compound was obtained (122 mg, yield 32%) as colorless crystals.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([O:29]C2CCCCO2)[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.CCOC(C)=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]1Cl
Temperature: 22 °C
Reaction time: 7.5 h

Procedure:
A 20 mL vial equipped with a magnetic stirbar was charged with 175 mg (0.34 mmol) of TAP-ether 8 dissolved in 5 mL of methanol. To this was then added 300 mg (1.20 mmol) of pyridinium p-toluenesulfonate and the mixture was stirred at 22° C. over 7.5 h. The reaction was sampled by TLC (Rf of product was 0.6 in EtOAc) and worked up by concentration in vacuo to remove methanol. The residual products were taken up in ethyl acetate and filtered through a 22 g plug of silica gel, eluting the polar product away from the salts with ethyl acetate (350 mL). Concentration of the filtrate yielded 125 mg of product triol 9 as an oil; 1H NMR (CDCl3): 1.18 (d, J=6.3 hz, 3H), 1.34-1.62 (m, 5H), 1.69 (m, 2H), 1.84-2.38 (m, 11H), 2.47 (br s, 1H), 3.53 (br s, 1H), 3.70 (br s, 1H), 3.79 (br m, 1H), 3.99 (m, 1H), 4.08 (m, 2H), 4.57 (m, 2H), 5.18-5.60 (m, 6H), 5.91 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].Cl>CC(O)C.C1COCC1>[C:11]1([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Oc1ccc(CCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of tyramine (3.0 g, 22 mmol) in 2-propanol (100 mL) and THF (50 mL) was added 4-phenylcyclohexanone 1 (3.8 g, 22 mmol) and 3 Å molecular sieves. After 2 hours, sodium borohydride (1.2 g, 31 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with MeOH, filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 CH2Cl2:MeOH) gave the free base which was converted to an HCl salt. Recrystallization from MeOH/Et2O gave the trans-isomer trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (0.98 g, 14%): mp 238-241° C.; IR (KBr): 2940, 1517, cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.99 (br d, 1H), 7.30-7.15 (m, 5H), 7.07 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 3.10-3.07 (m, 3H), 2.89-2.86 (m, 2H), 2.53-2.50 (m, 1H), 2.20 (d, J=20 Hz, 2H), 1.88 (d, J=20 Hz, 2H), 1.59-1.46 (m, 4H); CI—MS (methane) (m/z): 296 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C20H25NO, 296.2014; found, 296.2015; HPLC: method A, 5.83 minutes (100%); method B, 10.56 minutes (96.5%); Analysis Calcd for C20H25NO.HCl.0.25H2O: C, 71.41; H, 7.94; N, 4.16. Found: C, 71.29; H, 7.66; N, 4.12.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:34]([O:41][CH2:42][C:43]#[CH:44])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[C:45]1([C:33]2[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[O:41][CH2:42][C:43]#[CH:44])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: C#CCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: C#CCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-propargyloxybenzoic acid, and following the procedure described, 4-phenyl-3-propargyloxy-5-sulfamylbenzoic acid is obtained with a melting point of 154°-155° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:24]2([CH3:25])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@@H:14]([CH3:19])[CH2:15][C:16]([OH:18])=[O:17])[CH2:5][C@@H:4]([OH:27])[CH2:3]1.CO.[N+](=[CH2:32])=[N-]>C(O)(=O)C>[CH3:32][O:17][C:16]([CH2:15][C@H:14]([CH3:19])[C@@H:13]1[C@:20]2([CH3:26])[C@H:10]([C@H:9]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:25])[C:6]([CH2:5][C@@H:4]([OH:27])[CH2:3][C@@H:2]2[OH:1])=[CH:7][CH2:8]3)[CH2:11][CH2:12]1)=[O:18]
Reactant: C[C@@H](CC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C[C@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A solution of 1.0 g of (20S)-1α,3β-dihydroxy-20-methyl-pregn-5-ene-21-carboxylic acid in 50 ml. of methanol was treated with an ethereal solution containing 4 mmol of diazomethane and stored at room temperature for 30 minutes. After addition of glacial acetic acid, the mixture was concentrated in vacuo. The crystalline residue, which was uniform according to thin-layer chromatography, was recrystallised from concentrated methanolic solution to give 0.79 g of (20S)-1α,3β-dihydroxy-20-methyl-pregn-5-ene-21-carboxylic acid methyl ester in the form of colourless prisms of melting point 144°-146° C.; [α]D =-56° (c=0.5 in chloroform). Each mol of this ester contained 1 mol of methanol of crystallisation. EXAMPLE 16
Reaction SMILES: [I-].[CH:2]1([CH2:7]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reactant: c1ccc([PH](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphine iodide (725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The resulting red reaction mixture was stirred at 0° C. for 45 minutes and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction mixture was warmed to 25° C. where it was stirred for 20 h. The reaction mixture was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (Flash 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%) as a yellow oil consisting of a 2:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.[S:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[S:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:6]1[C:7](=[O:8])[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]=1[OH:5]
Reactant: C1=CSCC1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C2CCCS2)=C(O)C1
Reaction time: 0.5 h

Procedure:
A mixture of 7 parts of dimedone, 7 parts of 2,3-dihydrothiophene, 150 parts by volume of benzene and 0.7 parts of p-toluenesulfonic acid was refluxed by heating while stirring for 1 hour and 30 minutes and then allowed to stand at room temperature for 12 hours. The reaction mixture was washed with 50 parts by volume of water and then treated three times with 50 parts by volume of a 10% aqueous solution of sodium hydroxide. The aqueous layer was collected and the pH was adjusted to 2.0 with the addition of 6 N hydrochloric acid while maintaining the temperature thereof below 10° C. The light yellow colored crystals thus deposited were collected and purified by passing through a column containing a silica gel using a solvent mixture of chloroform and benzene (1:1) as a spreading agent to obtain 2-(2-tetrahydrothienyl)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one in a form of colorless fine crystals. The melting point was 97° to 99° C. The yield was 8 parts.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6](OC)[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])C.[CH3:17][NH:18][NH2:19]>>[F:12][C:7]([F:13])([C:6]1[N:18]([CH3:17])[N:19]=[C:4]([OH:3])[CH:5]=1)[C:8]([F:11])([F:10])[F:9]
Reactant: CCOC(=O)C=C(OC)C(F)(F)C(F)(F)F
Reactant: CNN
Product: Cn1nc(O)cc1C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 72 h
Yield: 29.8 %

Procedure:
62.03 g (0.25 mol) of 3-methoxy-3-pentafluoroethyl-2-propenoic acid ethyl ester was placed in a flask in ice water. 12.67 g (0.275 mol) of methylhydrazine was added with stirring keeping the temperature below 40° C. After the addition, the flask was removed from the ice bath and left standing for 3 days at ambient temperature. The reaction mixture was treated with 250 ml of aqueous sodium bicarbonate, washed with water, filtered and dried in vacuo to give 16.1 g (30% yield) of a white solid, m.p. 119°-124° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:10])[O:4][N:3]=1.[OH-].[Na+].[C:22](Cl)(=[O:33])[O:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1>C(Cl)Cl>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:22]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)=[O:33])[CH2:18][CH2:19]2)=[O:10])[O:4][N:3]=1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(CCc1cc(O)no1)NCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCc1cc(O)no1)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
3-(3-Hydroxyisoxazol-5-yl)-N-(2-(piperidin-4-yl)ethyl)propanamide (step 2) (201 mg, 0.662 mmol) was suspended in DCM (2 ml). 2M NaOH (1 ml, 2.00 mmol) was added and the reaction mixture stirred. To the mixture was added a solution of 3,5-dichlorobenzyl carbonochloridate (158 mg, 0.662 mmol) in DCM (1 ml) and the reaction mixture was stirred vigorously overnight. The resulting mixture was diluted with DCM and washed with citric acid. The organics were separated and evaporated under reduced pressure. The crude residue was dissolved in DMSO and purified by preparative HPLC. The product fractions were concentrated under reduced pressure and partitioned between EtOAc and water. The organics were separated, dried over MgSO4 (anh) filtered and evaporated under reduced pressure and dried in a high vacuum oven to afford the title compound;
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].CO.[OH-].[Na+].Cl>O>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COCCOCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
10 g (31.6 mmol) of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester, 100 ml of methanol and 31 ml of a 10 M NaOH solution are introduced, in order, into a 250 ml three-necked flask. The mixture is stirred at 80° C. for 30 minutes. After returning to room temperature, the reaction medium is poured over water and acidified with a 1 N HCl solution. The precipitate is filtered off. It is taken up in heptane. After filtering and drying, 9 g of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid are obtained in the form of a beige powder (yield=98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1c(F)cccc1F
Product: O=C(O)Cc1ccccc1Nc1c(F)cccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,6-difluoroaniline to yield 2-[(2,6-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[F:13][CH2:14][C:15]([CH2:17][F:18])=O.N1CCCC1>CO>[F:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([F:1])[CH:7]=1)[O:12][C:15]([CH2:17][F:18])([CH2:14][F:13])[CH2:10][C:9]2=[O:11]
Reactant: O=C(CF)CF
Reactant: CC(=O)c1cc(F)cc(F)c1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC(CF)(CF)Oc2c(F)cc(F)cc21
Yield: 80.9 %

Procedure:
A solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (4.98 g, 28.9 mmol), MeOH (50 mL), 1,3-difluoroacetone (5.44 g, 57.9 mmol), and pyrrolidine (4.79 mL, 57.9 mmol) was heated at 60° C. for 20 hours. The dark solution was cooled, concentrated, chased with toluene, and then passed through a silica gel plug, washing with toluene (200 mL) and MTBE (200 mL). The filtrate was washed with 2N NaOH (50 mL×2), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.80 g, 23.37 mmol, 81%), which was used without further purification in the next step. MS (DCI) m/z 299 (M+51)+.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([NH2:12])[N:5]=1.[CH2:14]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])[CH:18]=1)[CH3:15]>ClCCl>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([NH:12][C:31]([NH:30][S:27]([C:19]2[CH:18]=[C:17]([O:16][CH2:14][CH3:15])[CH:26]=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])(=[O:29])=[O:28])=[O:32])[N:5]=1
Reactant: COc1cc(OC(F)F)nc(N)n1
Reactant: CCOc1ccc(C(=O)OC)c(S(=O)(=O)N=C=O)c1
Solvent: ClCCl
Product: CCOc1ccc(C(=O)OC)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC(F)F)n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 4-difluoromethoxy-6-methoxypyrimidin-2-amine (0.56 g, 2.92 mmol) in dry dichloromethane (5 mL) was added a solution of methyl 4-ethoxy-2-(isocyanatosulfonyl)benzoate (crude, ca. 5.6 mL) in dichloromethane (5 mL). The reaction mixture was heated at reflux for 3 hours, during which time the solid dissolved. On stirring at room temperature for 12 hours a new solid formed. The crude reaction mixture was chromatographed directly on a column of silica gel using as eluant 40:1, 20:1, and finally 10:1 dichloromethane-ether, all containing 2 mL/L acetic acid. The appropriate fractions were diluted with toluene and rotary evaporated to give a solid. The solid was slurried in hexanes, collected, washed with butyl chloride, 1:1 butyl chloride-hexanes, hexanes and air dried. The product was a white crystalline solid melting at 195°-196° C. PMR (CDCl3, 200 MHz): δ 12.02 (bs, 1H); 7.91 (d, 1H); 7.78 (d, 1H); 7.52 (t, 1H); 7.34 (bs, 1H); 7.09 (dd, 1H); 5.97 (s, 1H); 4.17 (q, 2H); 4.12 (s, 3H); 3.87 (s, 3H); 1.46 (t, 3H). IR (Nujol): 1722 (vs, C=O) cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].ClC1C=C(C([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]2[O:34][CH2:35][CH2:36][CH3:37])=O)NC=1C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:22][C@@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@@H:24]2[O:34][CH2:35][CH2:36][CH3:37])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 2 g, 8.69 mmol) and ethyl (3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73, 1.59 g, 8.695 mmol) in dichloromethane (150 mL) was added N-Hydroxybenzotriazole (1.6 g, 10.43 mM) and N-methylmorpholine (2.63 g, 26.08 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-Ethyl-3-(3-dimethyl amino propyl)carbodiimide hydrochloride (2.87 g, 15.6 mM) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (50 mL) and the layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate 2.6 g (76%) as solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)=[O:15].CS(C)=O>C(#N)C>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)=[O:15]
Reactant: NC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CS(C)=O
Solvent: CC#N
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(N)=O)cc1
Temperature: 25 °C

Procedure:
2-(Methylamino)ethanol (9.5 g, 7 equivalents) is added to a stirred mixture of 4-[(8-bromooctanoyl)amino]benzamide (5.76 g, 16.9 mmol, e.g. which can be as prepared in Intermediate 53 (first or alternative preparation thereof)) and dimethyl sulfoxide (30 mL). The mixture is stirred at 25° C. until the reaction is substantially complete and is then diluted with acetonitrile (115 mL). After stirring for 1 hour the mixture is filtered, washed with ethyl acetate (15 mL) and tert-butyl methyl ether (TBME, 15 mL) before being dried in vacuo to yield the title compound, generally as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O)(=[O:22])C.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To 12.2 g (46 mmol) of 4-fluoro-4'-trifluoromethyltolane, 60 ml of water, 60 ml of acetic acid, 40 ml of sulfuric acid and 13.6 g (46 mmol) of mercuric sulfate were added, and the mixture was stirred at 90° C. for 3.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 5.1 g of 4'-fluoro-2- (4-trifluoromethylphenyl)acetophenone having a melting point of from 87° to 89° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CS(C)=O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCNC1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
Ethyl 4-fluorobenzoate (11.01 mL, 75 mmol) and 1,4-diazepane (30.0 g, 300.00 mmol) in DMSO (150 mL) warmed to 100° C. under nitrogen. The resulting solution was stirred at 100° C. for 24 h. The reaction mixture was cooled and evaporated to dryness. The reaction mixture was quenched with 2M NaOH (150 mL), extracted with EtOAc (3×75 mL), the organic layer was washed with saturated brine (100 ml), dried over MgSO4, filtered and evaporated to afford ethyl 4-(1,4-diazepan-1-yl)benzoate (17.43 g, 94%) as a colourless oil.