Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:25]([CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH3:24].C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:37]3[CH2:36][CH2:35][CH:34]([CH2:33][N:25]([CH2:23][CH3:24])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:39][CH2:38]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCN(Cc1ccncc1)CC1CCNCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CCN(Cc1ccncc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and ethyl-piperidin-4-ylmethyl-pyridin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (25%, off-white crystals). HPLC-MS m/z=515.2 (M+1), Rt: 2.77 min.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](=[S:37])[NH2:36])[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC(O)=O>CN(C=O)C>[C:25]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]2[S:37][C:2]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=4)[N:18]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=3[F:12])[N:36]=2)[CH2:33][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: CC(C)(C)N1CCC(C(N)=S)CC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(C)(C)C)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.276 g, 0.699 mmol, Preparation #A.2), 1-tert-butylpiperidine-4-carbothioamide (0.140 g, 0.699 mmol) and HOAc (0.080 mL, 1.40 mmol) were added to DMF (4 mL). The mixture was stirred at ambient temperature for about 1 h then at about 85° C. for about 1.5 h. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 N aqueous NaOH. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to an oil which was then purified by flash chromatography on silica gel using DCM/MeOH with 3% NH4OH (95:5) as an eluent to give the title compound: (0.077 g, 22%): LC/MS (Table 1, Method a) Rt=1.66 min; MS m/z: 497.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:16].[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1Cl
Yield: 25 %

Procedure:
A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (4.69 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (0.97 g), m.p. 149°-155° C.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])[CH:10]=1>C(O)=O>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][CH:5]=[O:7])[CH:10]=1
Reactant: Cc1cc(C)nc(-n2ccnc2SCc2ccccc2N)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1cc(C)nc(-n2ccnc2SCc2ccccc2NC=O)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
1.4 g of acetic acid anhydride are added to 2.5 ml of formic acid, and the mixture is stirred at 60° C. for 30 minutes. The reaction solution is cooled in an ice bath, a solution of 1.07 g of 1-(4,6-dimethyl-2-pyridyl)-2-(2-aminobenzylthio)imidazole in 4 ml of formic acid is added thereto, and the mixture is stirred at room temperature for 1 hour. After the reaction, the solvent is distilled off. Water is added to the residue, and the aqueous mixture is made alkaline with potassium carbonate. The mixture is then extracted with ethyl acetate, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:1). The crude crystals obtained above are recrystallized from a mixture of ethyl acetate and n-hexane, whereby 0.64 g of 1-(4,6-dimethyl-2-pyridyl)-2-(2-formylaminobenzylthio)imidazole is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][CH:7]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Oc2ccc(F)c(F)c2)nc1
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(F)c(F)c3)nc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].[O:24]=[C:25]1[N:34]([CH:35]2[CH2:40][CH2:39][N:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]2)[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1>>[O:23]=[C:3]1[C@H:2]([NH:1][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([N:34]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:24])[CH2:36][CH2:37]2)=[O:42])[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]1[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@H](N)CCC[C@@H]1c1ccccc1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Product: CC(C)(C)OC(=O)CN1C(=O)[C@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)CCC[C@@H]1c1ccccc1

Procedure:
The title compound was prepared with tert-butyl [(3R,7R)-3-amino-2-oxo-7-phenylazepan-1-yl]acetate and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 1. MS 576 (M+1).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.S(=O)(=O)(O)O>O1CCCC1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 66.2 %

Procedure:
A solution of 8.7 g of 11β-fluoro-7α-methyl-estr-4-ene-3,17-dione in 148 ml of tetrahydrofuran was mixed drop by drop at 0° C. with 29.5 ml of 1 M lithium aluminium tri-tert-butoxyhydride in tetrahydrofuran and stirred for 5.5 hours at 0° C. Then, dilute sulfuric acid was added at 0° C., and the reaction solution was added to ice water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 5.8 g 11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one with a melting point of 143-144° C. was obtained. [α]D=+89.9° (CHCl3).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31](OC)=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>O1CCCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:26][CH2:27]1)=[O:32]
Reactant: c1ccc2scnc2c1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Temperature: -78 °C

Procedure:
Dissolve freshly distilled benzothiazole (3.41 g, 25.24 mmol) in anhydrous tetrahydrofuran (60 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, n-butyllithium (15.14 mL of a 2.5M solution in hexane, 37.86mmol) and stir briefly at -78° C. Add, by dropwise addition, a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (7.0 g, 25.24 mmol) in anhydrous tetrahydrofuran (40 mL). Stir for 1 hour at 78° C., quench with methano 1 (5 mL) and pour into saturated ammonium chloride (100 mL). Filter, separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phase s and wash with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) and recrystallize (cyclohexane) to give the title compound as a pale yellow powder; mp 118°-120° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:23])[CH2:4][C@@:5]23[CH2:18][CH2:17][N:16]([CH3:19])[C@@H:13]([C@@H:14]2[CH:15]=1)[CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:20][CH3:21])=[C:7]([OH:22])[C:6]3=1.[NH4+].[Cl-].[NH4+].[OH-].[CH2:28](Cl)Cl>CCOCC>[OH:22][C:7]1[C:6]2[C@:5]34[CH2:18][CH2:17][N:16]([CH3:19])[C@@H:13]([C@@H:14]3[C@@H:15]([CH3:28])[C@H:2]([CH3:1])[C:3](=[O:23])[CH2:4]4)[CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1C=C(C)C(=O)C3
Reactant: ClCCl
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1[C@@H](C)[C@H](C)C(=O)C3
Reaction time: 1 h

Procedure:
Compound 14 (20.0 g, 64 mmole) in methylene chloride (400 ml) was added to a solution of lithium dimethyl cuprate (165 mmole) prepared in ether (800 ml) with cooling in an ice-salt bath under an argon atmosphere. The mixture was stirred at this temperature for 1 hour after which it was poured into saturated NH4Cl solution (1 liter). After the addition of concentrated NH4OH to pH~12 and stirring for 30 minutes, the organic phase was separated and washed twice with dilute NH4OH. The aqueous phase was extracted with additional methylene chloride and the combined organic phases dried and evaporated to give a quantitative yield of 16b as a thick syrup, NMR: δ 6.63, s, 2H (aromatic); 4.25, d, 1H (H-5α, J=13H); 3.80 (CH3O--); 2.43 (CH3N--); 1.08; unsymmetrical t, 3H (8β-CH3, J=6H); 0.90, symmetrical d, 3H (7α-CH3, J=6H). A portion of this material was converted to the hydrochloride salt by dissolving the syrupy free base in ethanol and adding excess concentrated HCl. The solution was evaporated to dryness and the residue azeotroped with ethanol, 1:1 V/V ethanol:benzene, then benzene. The residue was crystallized from ethyl acetate to give 16b HCl, mp 259°-262°.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])C.[C:26]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38][O:39]S(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:50][C:34]1[O:33][C:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:36][C:35]=1[CH2:37][CH2:38][O:39][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:25])=[O:3])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCCCC(Cc1ccc(O)cc1)(Oc1ccccc1)C(=O)OCC
Product: CCCCC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(4-hydroxybenzyl)-2-phenoxy-hexanoic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.42-7.40 (m, 3H), 7.31-7.27 (m, 2H), 7.06 (t, 1H, J=7.43 Hz), 6.98 (t, 4H, J=8.99 Hz), 6.75 (d, 2H, J=8.60 Hz), 4.17 (t, 2H, J=6.65 Hz), 3.29 (s, 2H), 2.96 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 2.10-1.98 (m, 2H), 1.42-1.16 (m, 4H), 0.79 (t, 3H, J=7.04 Hz); MS (ES+) calcd for C31H34NO5: Found m/e 500.2 (M+1, 100%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[C:33](N1C=CN=C1)([N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)=[O:34].C(OCC)(=O)C>O>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:33]([N:35]3[CH:39]=[CH:38][N:37]=[CH:36]3)=[O:34])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CN1C(=O)C(NC(=O)n2ccnc2)N=C(c2ccccc2F)c2ccccc21)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl]carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.2 g) and carbonyldiimidazole (895 mg) was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, and organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The amorphous powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(imidazol-1-yl) carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.43 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[O:23][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A mixture of 2,4-dibenzyloxyphenol (3.1 g) and sodium hydride (0.44 g, 60% dispersion in mineral oil) in THF (75 mL) is refluxed for 30 minutes then refluxing is allowed to abate. Neat ethyl bromoacetate (1.8 g) is added and refluxing continued for 1 hour. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is washed with water (100 mL), dried o ver magnesium sulphate, filtered and concentrated in vacuo to give a light brown oil. Flash chromatography of the residue eluting with dichloromethane affords ethyl 2,4-dibenzyloxyphenoxyacetate (3.2 g) after trituration with pentane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([C:33]#[N:34])=[N:26][C:27]([CH:30]2[CH2:32][CH2:31]2)=[CH:28][CH:29]=1)=[N+]=[N-].O1CCCC1>O>[CH:30]1([C:27]2[N:26]=[C:25]3[C:33]([NH2:34])=[N:20][CH2:23][C:24]3=[CH:29][CH:28]=2)[CH2:32][CH2:31]1
Reactant: N#Cc1nc(C2CC2)ccc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1=NCc2ccc(C3CC3)nc21
Reaction time: 3 h
Yield: 90.4 %

Procedure:
Triphenylphosphine (365 mg, 1.39 mmol) was added at room temperature to a solution of the 3-(azidomethyl)-6-cyclopropyl-2-pyridinecarbonitrile (230 mg, 1.15 mmol) in a tetrahydrofuran (4 ml) —H2O (0.2 ml) mixed solvent and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, to yield the title compound (180 mg, 90%) as a white amorphous solid from the ethyl acetate-methanol-29% NH3(aq) (30:10:1) elution fraction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Br:16]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Br:16])[C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4-hydroxyisophthalic acid dimethyl ester (10.51 g) in THF (100 mL) was added N-bromosuccinimide (9.34 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (200 mL) and saturated aqueous sodium bicarbonate (100 mL) were successively added to the reaction solution. The resulting precipitate was filtered, washed successively with saturated aqueous sodium bicarbonate and water, and dried to give the title compound (12.5 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:25]=1[Cl:26]>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([NH:7][CH:4]([CH2:5][OH:6])[CH:3]([C:8]([F:9])([F:10])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:29])=[O:28])[S:24][C:25]=1[Cl:26]
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
A solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (0.192 g, 0.9 mmol) in THF (1 mL) was stirred under nitrogen at 25° C. Pyridine (0.147 mL, 1.82 mmol) was added followed by 4,5-dichlorothiophene-2-sulfonyl chloride (0.226 g, 0.391 mmol) in THF (1 mL), and the resulting solution stirred for 18 h at 25° C. After concentration, the residue was taken up in EtOAc (15 mL) and washed with 1 N aq. HCl (10 mL), brine (10 mL), and then dried (Na2SO4). After concentration, the crude product was purified by preparatory TLC, eluent: 30:70 EtOAc:hexanes, to provide 4,5-dichloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (0.037 g, 9% yield, racemic mixture). Mass Spectrum (−ESI): 423.9 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:35]([C:27]3[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([C:24]([F:23])([F:39])[F:40])[CH:26]=3)(=[O:37])=[O:36])[C:13]=2[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of (5-amino-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (125.0 mg, 0.38 mmol) and 3,5-di-(trifluoromethyl)benzene-1-sulfonyl chloride (0.117 g, 0.38 mmol) in dry tetrahydrofuran (5 mL) was added diisopropylethylamine (0.2 mL, 0.94 mmol) at 0° C. under nitrogen. After 2 hours of stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The collected organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in hexane) gave [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (163.2 mg, 71%). MS cald. for C24H23ClF7NO5S 605, obsd. 604 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24]O.C(C=P(CCCC)(CCCC)CCCC)#N>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:24][C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[C:6]2=[N:7][CH:8]=1
Reactant: OCc1nccs1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1nccs1
Yield: 83.1 %

Procedure:
This compound was prepared according to a process similar to that described in step 5.1. by reacting 390 mg (1.51 mmol) of ethyl 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (WO2008/107543) with 348 mg (3.02 mmol) of thiazol-2-ylmethanol in the presence of 0.92 g (3.826 mmol) of (cyanomethylene)-tributylphosphorane (CMBP). The reaction mixture is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate to give 446 mg of the expected product in the form of an oil.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[C:11]([C:14]#[N:15])[C:12]#[N:13])SC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:17][NH2:18]>CCO>[NH2:13][C:12]1[NH:18][N:17]=[C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:14]#[N:15]
Reactant: NN
Reactant: CSC(NC1CCCCC1)=C(C#N)C#N
Solvent: CCO
Solvent: O
Product: N#Cc1c(NC2CCCCC2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((cyclohexylamino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(cyclohexylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH3:11][Si](C=[N+]=[N-])(C)C.CO>CC(OC)(C)C>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH3:11]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: COC(C)(C)C
Solvent: CO
Product: COc1c(I)cc(I)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 250 mL pressure vessel was added 2,4,6-triiodophenol (5 g, 10.60 mmol) in MTBE (60 ml) to give a yellow solution. The solution was cooled in an ice bath and 2.0M trimethylsilyldiazomethane (7.95 ml, 15.90 mmol) was added at a fast drip followed by dropwise addition of methanol (6 mL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 4 h. The reaction solution was partitioned between EtOAc and water and the organic layer was washed with 1M HCl, saturated NaHCO3, and saturated NaCl. The EtOAc was dried (MgSO4), filtered and concentrated to give a tan solid that was used without purification (4.8 g, 94%).