Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Te:1]([Cl:5])(Cl)(Cl)[Cl:2].[C:6]1([O:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>>[CH3:13][O:12][C:6]1[CH:11]=[CH:10][C:9]([Te:1]([Cl:5])([Cl:2])[C:9]2[CH:10]=[CH:11][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: Cl[Te](Cl)(Cl)Cl
Reactant: COc1ccccc1
Agent: Cl
Product: COc1ccc([Te](Cl)(Cl)c2ccc(OC)cc2)cc1
Yield: 87 %

Procedure:
Tellurium tetrachloride (7.50 g, 28 mmol) and anisole (15 g, 139 mmol) were stirred at 180° for 18 h under a slow stream of nitrogen. After this time 48 mmol of hydrogen chloride had been evolved and the excess anisole was removed under high vacuum. The remaining brown solid was recrystallised from benzene to afford bis-(p-methoxyphenyl)tellurium dichloride (10.05 g, 88%), m.p. 181°-182° (lit., 181°-182°), δ(CDCl3) 8.01 (4H,d,J 9 Hz), 7.03 (4H,d,J 9 Hz) and 3.89 (6H,s).
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:33]([N:27]1[CH2:28][CH:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH:9]2[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S1(=O)C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
2 drops of trifluoroacetic acid are added to a solution of 1.3 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide and 1.75 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 12 cm3 of anhydrous dichloromethane, and the mixture is stirred for 30 minutes at 30° C. 1.75 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine and 2 drops of trifluoroacetic acid are again added and the mixture is stirred for 2 hours at 35° C. This last procedure is once again repeated and after stirring for 1 hour, 1 g of potassium carbonate is added. The suspension is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 35 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (80/20 by volume) and collecting fractions of 30 cm3. Fractions 20 to 28 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (4aRS,7aRS)-6-benzyl4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals; melting point 186° l C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:19]C1CC(C(C)C)CCC1=O>>[CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][C:9](=[O:12])[CH:10]([Br:19])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CCOC(=O)C1(c2ccccc2)CCC(=O)CC1
Product: CCOC(=O)C1(c2ccccc2)CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-1-phenyl-cyclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.N1C2=C(OC3C=CC(N[C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[S:38])=CC=3F)N=CC=C2C=C1>>[Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[S:38])=[CH:14][C:13]=2[F:19])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Yield: 99 %

Procedure:
Starting from the compound 273 and following the procedure described above for the synthesis of compound 262a (scheme 59, example 218, step 4), title compound 274 was obtained in 99% yield as a white solid. 1H NMR (DMSO-d6) δ (ppm):12.44(s, 1H), 11.79(s, 1H), 8.82(s, 1H), 8.03(d, 1H), 7.99(dd, 1H), 7.54(d, 1H), 7.41(dd, 1H), 7.32-7.24(m, 6H), 3.80(s, 2H). MS (m/z):517.0 (M+H) (found).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([NH:11][C:12]2[C:13](=[O:29])[N:14]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:16][N:17]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][Cl:39]>C(#N)C>[Cl:39][CH2:38][CH2:37][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([NH:11][C:12]2[C:13](=[O:29])[N:14]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:16][N:17]=2)[CH2:9][CH2:10]1
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4OCCCl)CC3)c2=O)c1
Temperature: 83 °C
Reaction time: 10 h

Procedure:
A solution of methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167c) 0.45 g) dissolved in acetonitrile (8 mL) was treated with potassium carbonate (1.589 g) and 1-bromo-2-chloroethane (0.953 mL) under nitrogen. The resulting suspension was stirred at 83° C. for 10 h.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:73][CH2:74][C:75]1[NH:79][N:78]=[N:77][N:76]=1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:73][CH2:74][C:75]4[NH:79][N:78]=[N:77][N:76]=4)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1nnn[nH]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nnn[nH]1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.9 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (135 mg, 0.24 mmol) in CH2Cl2 (1 mL) were added N,N-diisopropylethylamine (170 μL, 0.98 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol), 1-hydroxybenzotriazole (47 mg, 0.35 mmol), and 5-(aminomethyl)tetrazole (33 mg, 0.33 mmol). The suspension was allowed to stir at r.t. for 23 hr, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→30% MeOH in CH2Cl2) to afford the title compound as a yellow solid (70 mg, 46% yield). LC/MS (ESI) retention time: 1.61 min, m/z 635 (MH+); 1H NMR (400 MHz, CD3OD) δ 1.08-1.23 (m, 1 H) 1.35-1.48 (m, 4 H) 1.66 -1.79 (m, 3 H) 1.86 -1.92 (m, 1 H) 1.96 -2.14 (m, 3 H) 2.44-2.60 (m, 5 H) 2.74 -2.89 (m, 2 H) 3.16 (dd, J=7.55 Hz, 1 H) 3.57 -3.73 (m, 5 H) 4.25 (s, 1 H) 4.94-5.08 (m, 1 H) 6.87 (s, 1 H) 7.43-7.51 (m, 3 H) 7.52-7.59 (m, 2 H) 7.83 (d, J=8.56 Hz, 1 H) 8.11 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:27][C:8]2=[C:9]3[C:14](=[C:15]([O:17]C)[CH:16]=[C:7]2[CH:6]=1)[N:13]=[C:12]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=[C:10]3[C:23]([O:25][CH3:26])=[O:24])=[O:4].[OH2:28]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[NH:27][C:8]2[C:9]3[C:10]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:12]([C:19]([O:21][CH3:22])=[O:20])=[N:13][C:14]=3[C:15](=[O:17])[C:16](=[O:28])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)OC)c2c(n1)c(OC)cc1cc(C(=O)OC)[nH]c12
Reactant: O
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C(=O)c1cc(C(=O)OC)[nH]c1-2
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (about 250 g, 0.67 mol) in acetonitrile (ACN) (about 7.5 L), a solution of ceric ammonium nitrate (about 1.83 kg, 3.35 mol) in about 2.25 L of water is added over a period of about 30 minutes at about −5° C. The reaction mixture is stirred at about −5° C. over a period of about 1.5 hours. Thereafter, resulting reaction mass is filtered, washed with water and dried to obtain the product [4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester] as a bright orange solid (about 145 g, 58%). 1H NMR (DMSO-d6, 300 MHz): 3.90 (s, 3H), 3.97 (s, 3H), 4.05 (s, 3H), 7.29 (d, J=1.8 Hz, 1H), 8.56 (s, 1H), 12.52 (s, 1H); LC-MS (ESI): 373.0 (M-H).
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[CH:4]=[CH:5][C:6]([N+:36]([O-:38])=[O:37])=[C:7]([N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=1>CCCCCC.C(OCC)(=O)C>[CH2:1]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([N+:36]([O-:38])=[O:37])=[C:7]([N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1cc(N(C)C)ccc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1cc(NCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
tert.butyl 4'-[N-(5-dimethylamino-2-nitrophenyl)-pentanoylaminomethyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Silica gel: hexane/ethyl acetate=4:1).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCCCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCSc1nc2ccccc2n1CC(=O)O
Yield: 83 %

Procedure:
A solution of tert-butyl[2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor E-01b, 44 mg, 0.11 mmol) in TFA/dichloromethane (1:1, 2 ml) is stirred at rt for 3 h. The solvents are removed under a stream of air. The solid residue is suspended in Et2O (2 ml) and sonicated. Filtration, rinsing with Et2O and drying under high vacuum yields the title compound (32 mg) as a white solid in 85% yield: tR=5.33 min (LC-1), ESI-MS (pos.): m/z 351.07 [M+H]+, ESI-MS (neg.): m/z 349.22 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H CH3), 1.44 (s, 9H, tBu), 1.32-1.44 (m, 2H), 1.52-1.70 (m, 4H), 2.24 (t, 2H, CH2C═O), 3.24 (t, 2H, SCH2), 4.10 (q, 2H, OCH2), 4.15 (br. s, 1H, CO2H), 4.86 (s, 2H, CH2CO2), 7.24 (s, 3Harom), 7.63 (m, 1Harom).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32](S(C)=O)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32]([O:10][CH2:9][CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCc2ccccn2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of 2-pyridinepropanol (0.960 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.141 g, 34%). Mass (m/z): 417.2 (M++1), 415.1 (M+−1).
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[N:1]1([C:8]2[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(azepan-1-yl)-2-phenylquinoxaline-6-carboxylate (132.4 mg, 0.37 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (73.4 mg, 1.83 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 80 mg (61%) of 3-(azepan-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(F)c(C2=CCSCC2)c(F)c1)OCc1ccccc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
4-(4-Amino-2,6-difluorophenyl)-5,6-dihydro-2H-thiopyran (15.0 g, 66 mM) was dissolved in dry dichloromethane (250 ml), pyridine (9.45 g, 113 mM) added, and the whole stirred under nitrogen at −20°. Benzyl chloroformate (17.1 g, 100 mM) in dry dichloromethane (25 ml) was added dropwise, and the mixture allowed to warm to ambient over 18 hours. The mixture was washed with hydrochloric acid (1M, 2×200 ml), then brine (200 ml) and dried (magnesium sulfate). Evaporation to a small volume and dilution with isohexane gave the desired product as a white solid (22.5 g).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.O.[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(OCC)(=O)C>[CH3:14][S:15]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:17])=[O:16]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)On1nnc2ccccc21

Procedure:
1-Hydroxy-1,2,3-benzotriazole (25.7 g) is suspended into water (50 ml) and thereto is added 1 N aqueous sodium hydroxide (180 ml). To the resulting solution is added dropwise methanesulfonyl chloride (14.0 ml) with stirring under ice-cooling and thereto is further added ethyl acetate (30 ml), and the mixture is stirred for 4 hours. The reaction mixture is extracted with ethyl acetate, and the extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and to the resulting residue is added petroleum ether, and the residue is cracked, filtered and dried to give 1-methanesulfonyloxy-1,2,3-benzotriazole (39.1 g), melting point: 88°-91° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:7]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=2)O1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)[CH:3]=[CH:4][C:5]=1[CH3:14])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: Cc1ccc(Br)cc1NC(=O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)C(C)C

Procedure:
Prepared by Procedure W and Scheme AF using N-(5-bromo-2-methylphenyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 259.1 (M - 100)+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.[F:13][C:14]1[CH:15]=[C:16]([NH:32][C:33]([C:35]2[C:36](=[O:48])[N:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:38]([CH3:41])[C:39]=2[CH3:40])=[O:34])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([NH:32][C:33]([C:35]2[C:36](=[O:48])[N:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:38]([CH3:41])[C:39]=2[CH3:40])=[O:34])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:5][CH2:6][CH2:7][CH2:8][C:9]3([OH:12])[CH2:11][CH2:10]3)=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.8 %

Procedure:
To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (240 mg, 1.2 mmol) and N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (470 mg, 2.4 mmol). After stirring at rt for 12 hrs, then the mixture was warmed up to 40° C. and stirred for 6 hrs. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (40 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (5:1 (v/v) EtOAc/n-hexane) to afford the desired compound as a white solid (68 mg, 19%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:28][C:25]2[CH:26]=[CH:27][N:22]=[N:23][CH:24]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(Nc1ccnnc1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 4-pyridazinamine (CAN 20744-39-2, 31.4 mg, 0.33 mmol) as starting materials; off white solid (60 mg, 47.8%). MS (ESI): 381.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]2)(=[O:10])=[O:9])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:31][C:32]([F:36])([F:35])[CH2:33][O:34][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]2)(=[O:9])=[O:10])=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Under an atmosphere of argon, (2S,4R)-1-tert-butyl 2-methyl 4-(4-fluoro-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-1,2-dicarboxylate ([prepared in analogy to General Procedure C, steps C1-C3, using 2-trifluoromethyl-4-fluorothiophenol in step C2] 0.79 g, 1.73 mmol, Eq: 1.00) was combined with N,N-dimethylacetamide (10 ml) to give a light yellow solution. 2,2,2-Trifluoroethanol (416 mg, 301 μl, 4.16 mmol, Eq: 2.4) and cesium carbonate (1.02 g, 3.12 mmol, Eq: 1.8) were added. The reaction mixture was stirred over night at RT. The crude reaction mixture was concentrated in vacuo. The residue was poured into HCl (0.5 M, 20 ml) and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% ethyl acetate in heptane) to yield the title compound as a white foam (610 mg, 65.7%, MS (m/e)=536.1 [M+H+]).
Reaction SMILES: ClC(OC(Cl)C)=[O:3].[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCCl>[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][CH:27]=2)[C:16]1=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)(C)c1ccc(CC2CN(Cc3ccccc3)CCO2)cc1
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(CC2OCCN(Cc3ccccc3)C2=O)cc1

Procedure:
1-Chloroethyl chloroformate (2.98 ml, 27.7 mmol) was added in a steady stream to a stirred solution of the N-benzyl-2-(4-tert-butylphenylmethyl)morpholine (8.94 g, 27.7 mmol) obtained in (ii) in 1,2-dichloroethane (100 ml) at 0° C. The reaction was stirred for 20 minutes and then heated under reflux for 135 minutes before cooling and evaporation in vacuo. Methanol (100 ml) was then added and the reaction heated under reflux for 1 hour before cooling, evaporation in vacuo and dissolution in chloroform (about 200 ml). This solution was washed with saturated aqueous sodium hydrogen carbonate (20 ml), dried with sodium sulphate and evaporated in vacuo. The resulting gummy solid was recrystallised from chloroform/diethyl ether to afford the desired product as a white solid, 1.5 g, M.pt. 190°-193° C., M+ --HCl found: 233.