Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([OH:7])=O.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[Br:23][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:31]1[CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=[CH:29][C:30]=1[S:33]([NH2:36])(=[O:34])=[O:35])=[O:7]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc([N+](=O)[O-])ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 37.2 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (, 0.035 mmol) was coupled with 4-nitrophenylsulfonamid (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 8 mg (37%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([C@@H:29]2[CH2:33][O:32]C(C)(C)[O:30]2)([CH3:28])[CH3:27])[N:12]=1>C(Cl)Cl.C(=O)([O-])O.[Na+].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([CH3:28])([CH3:27])[C@@H:29]([OH:30])[CH2:33][OH:32])[N:12]=1
Reactant: CC1(C)OC[C@@H](C(C)(C)Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product from step iii) (0.37 g) in DCM (10 mL) was added iron (III) chloride hexahydrate (0.66 g) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with sat. sodium hydrogencarbonate solution and extracted with DCM (×3). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using a MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white solid. Yield: 0.16 g
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:28]3=[N:29][CH:30]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.[Br:43]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:43][C:32]1[N:31]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=[C:25]([CH2:24][CH2:23][C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:26]=[C:27]2[CH:33]=1
Reactant: COc1cc(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.610 mL, 4.25 mmol) in tetrahydrofuran (2.0 mL) at −78° C., n-butyllithium (2.5 M in hexanes, 1.70 mL, 4.25 mmol) was added dropwise. After the white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting resulted solution was added to a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (1.30 g, 3.07 mmol) in tetrahydrofuran (10 mL) at 78° C. After 30 min, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (1.10 g, 3.38 mmol) in tetrahydrofuran (6 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (1.30 g, 84%). LCMS calculated for C22H21BrN3O4S (M+H)+: m/z=502.0. Found: 502.0; 1H NMR (400 MHz, CDCl3): δ 8.15-8.12 (m, 3H), 7.68-7.58 (m, 1H), 7.51-7.47 (m, 2H), 6.88 (s, 1H), 6.31 (d, J=2.0 Hz, 2H), 6.28 (t, J=2.5 Hz, 1H), 3.72 (s, 6H), 3.16-3.12 (m, 2H), 2.99-2.96 (m, 2H) ppm.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:30]([O:32][CH3:33])=[O:31])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:33][O:32][C:30](=[O:31])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
In a similar manner, 2.77 grams of 80 percent pyridinium bromide perbromide (6.93 millimoles) was added in one portion to a cooled to 0° C. solution of 2.00 grams (5.77 millimoles) of dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nifedipine), and 0.81 milliliter of pyridine in 40 milliliters of chloroform. The resulting mixture was stirred at 0° C. for 30 minutes, at reflux temperature for 90 minutes, allowed to cool to room temperature, diluted with chloroform, washed with 2N hydrochloric acid and with brine, dried, and the solvent vaporized in vacuo to obtain a crude product residue. The latter was flash chromatographed (J. Org. Chem. 43, 2923 (1978)) on silica gel employing 70 percent ethyl acetate--30 percent hexane as eluant to obtain 0.45 gram (24 percent yield) of purified methyl 2-methyl-4-(2-nitrophenyl)-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]-pyridine-3-carboxylate product which after recrystallizing from ethyl acetate hexane had a melting point of 261°-263° C. (dec.). Elemental analyses were as follows:
Reaction SMILES: NC1N=C2C=CC(C3C=C(NS(C)(=O)=[O:19])C(Cl)=NC=3)=NN2C=1C1C=CC=C(F)C=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:43]([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[C:52]([C:57](N5CCOCC5)=[O:58])[CH:51]=4)=[C:44]([NH:46]C(=O)C)[N:45]=3)[N:42]=2)=[CH:33][C:32]=1[NH:65][S:66]([CH3:69])(=[O:68])=[O:67].[OH-].[Na+]>>[NH2:46][C:44]1[N:45]=[C:40]2[CH:39]=[CH:38][C:37]([C:34]3[CH:35]=[N:36][C:31]([Cl:30])=[C:32]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[CH:33]=3)=[N:42][N:41]2[C:43]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[C:52]([CH:51]=1)[C:57]([OH:58])=[O:19]
Reactant: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4cccc(F)c4)n3n2)cnc1Cl
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1ccc(F)c(C(=O)N2CCOCC2)c1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4ccc(F)c(C(=O)O)c4)n3n2)cnc1Cl
Reaction time: 0.33 h
Yield: 27 %

Procedure:
Following the procedure described for N-(5-(2-amino-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)methanesulfonamide (Example 23), N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (TFA salt) (Example 24) (0.016 g, 0.023 mmol) was treated with sodium hydroxide (0.100 mL, 1.0 mmol, 10 M) and purified by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.), C18, 100×30 mm, 5 to 85% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min then 100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) with the fractions containing suspected product concentrated to afford the title compound as a yellow solid (3.6 mg, 27%). MS (ESI, positive ion) m/z: 477 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.19 (s, 3H), 6.00 (br s, 2H), 7.40-7.45 (m, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 8.23-8.28 (m, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.47-8.50 (m, 1H), 8.93 (d, J=2.0 Hz, 1H), 9.85 (s, 1H), 13.28 (br s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH:39]2[CH2:44][CH2:43][CH:42]([C:45]3[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]4[C:46]=3[CH2:47][N:48]([CH3:56])[C:49]4=[O:55])[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([C@H:39]2[CH2:40][CH2:41][C@H:42]([C:45]3[CH:53]=[CH:52][C:51]([NH:54][C:2]4[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]5[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=5[O:28][CH3:29])[N:3]=4)=[C:50]4[C:46]=3[CH2:47][N:48]([CH3:56])[C:49]4=[O:55])[CH2:43][CH2:44]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CC(=O)N1CCN(C2CCC(c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](N5CCN(C(C)=O)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compounds were prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 4-[4-(4-acetyl piperazin-1-yl)cyclohexyl]-7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 237A). The reaction mixture was purified by MDP. Example 237 was first peak to elute. 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=6.95 Hz, 6 H), 1.50-1.73 (m, 7 H), 2.02 (s, 2 H), 2.12 (s, 3 H), 2.50 (br. s., 2 H), 2.62 (br. s., 3 H), 3.13-3.21 (m, 2 H), 3.22 (s, 3 H), 3.42-3.75 (m, 4 H), 3.93 (s, 3 H), 3.99-4.10 (m, 4 H), 4.38 (s, 2 H), 6.90 (dt, J=8.08, 2.15 Hz, 1H), 6.94 (t, J=2.02 Hz, 1 H), 7.34 (d, J=8.84 Hz, 1 H), 7.63 (s, 1 H), 8.28 (d, J=7.58 Hz, 1H), 8.40 (s, 1 H), 8.64 (d, J=8.59 Hz, 1 H), 10.51 (s, 1 H). MS (ES+): m/z 788.31 [MH+] (TOF, polar). Example 238 eluted afterwards: 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=7.07 Hz, 6 H), 1.87 (d, J=4.04 Hz, 2 H), 1.91-2.03 (m, 2 H), 2.12-2.25 (m, 7 H), 2.84 (br. s., 2 H), 3.21 (s, 3 H), 3.23-3.33 (m, 4 H), 3.86 (s, 3 H), 3.93 (br. s., 2 H), 4.04 (qdd, J=7.31, 7.31, 7.31, 7.14, 1.77 Hz, 4 H), 4.38 (s, 2 H), 6.94-7.00 (m, 2 H), 7.36 (d, J=7.83 Hz, 1 H), 7.71 (br. s., 1 H), 8.23 (br. s., 2 H), 11.20 (br. s., 1 H). MS (ES+): m/z 788.31 [MH+] (TOF, polar).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH2:15])=[C:10]([CH3:16])[CH:9]=1.O>C(#N)C>[CH2:5]([O:4][C:2](=[O:3])[NH:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[CH3:16])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Nc1c(C)cc(Br)cc1C
Yield: 97 %

Procedure:
Ethyl chloroformate (0.55 g, 0.48 mL, 5 mmol) was added to a solution of 4-bromo-2,6-dimethyl-phenylamine (1.0 g, 5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at reflux for 16 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.32 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:5]
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)O)c(Cl)cc3F)c1=O)CCC2
Solvent: CC(C)(C)O
Product: Cn1c2c(c(=O)n(-c3cc(C(=O)OC(C)(C)C)c(Cl)cc3F)c1=O)CCC2

Procedure:
using 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoic acid via the corresponding acid chloride and tert.butanol there is obtained tert.butyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.76 ppm (d, 1H), 7.31 ppm (d, 1H), 3.41 ppm (s, 3H), 2.94 ppm (m, 2H), 2.81 ppm (m, 2H), 2.17 ppm (m 2H), 1.57 ppm (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:59]=[CH:58][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C@H:45]3[F:57])=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:14]([C:10]5[C:9](=[O:17])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH:13]=[CH:12][N:11]=5)=[O:16])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:46][C@H:45]3[F:57])=[N:26]2)=[CH:58][CH:59]=1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1

Procedure:
Prepared from 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (190 mg, 0.811 mmol, prepared according to the procedure for Example 125, Step E) and ±(3R*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (157 mg, 0.270 mmol, obtained from Example 145, Step A) according to the procedure described for Example 145, Step B. Yield: 138 mg (51%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 76.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.26 g, 0.44 mmol) prepared in Example 58a, triethylsilane (0.35 mL), trifluoroacetic acid (0.44 mL) and dichloromethane (4.4 mL), to yield the title compound (0.15 g, 77%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22]Cl>CN(C)C=O>[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: ClCC=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(C(F)(F)F)cc1
Yield: 48.9 %

Procedure:
Using 0.45 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 0.28 g of 2-(3,3-dichloro-2-propenyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (55)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(O)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)c1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of 44 (2.65 g, 10 mmol) in DMF (20 mL) was added sodium hydride (60% dispersion in mineral oil, 0.88 g, 22 mmol). After gas evolution ceased 4-fluorobenzaldehyde (1.60 g, 15 mmol) was added and the reaction was stirred for 16 h. The mixture was poured over 10% citric acid (100 mL), after which a bright yellow solid formed. The solid was washed with water and then the wet solid was azeotroped and recrystallized from toluene to yield 2.97 g (80%) of a yellow solid 45.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:19](=[O:44])[N:18]([CH3:45])[C:17]=2[N:16]=1>CN(C=O)C.O>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:38])[CH3:39])[C:19](=[O:44])[N:18]([CH3:45])[C:17]=2[N:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
Step 1 Diethyl malonate (0.35 mL, 2.31 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% in oil, 0.74 g, 1.85 mmol) was added portion wise. The mixture was stirred for 15 min and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.92 mmol, intermediate 77) was added. The reaction was heated at 100° C. for 15 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column eluted with 20% ethyl acetate/hexanes to give diethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)malonate (0.23 g, 40% yield) as a clear oil. LCMS retention time=5.015 min and 95% purity, LCMS MH+ 621. 1H NMR (DMSO-d6) δ 7.27 (dd, 4H, J=8 Hz and 72 Hz), 5.62 (d, 2H, J=12 Hz), 5.54 (s, 2H), 5.61 (s, 1H), 3.90-4.03 (m, 6H), 3.62 (t, 2H, J=8 Hz), 3.37 (s, 3H), 1.70-1.78 (m, 2H), 1.08 (t, 6H, J=8 Hz), 0.80 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](S(Cl)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:32])([F:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:32][C:14]([F:13])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCCN3)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C

Procedure:
582 mg of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 5 ml pyridine. Then 400 mg 6-(4-Trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline were added and the mixture was stirred at room temperature for thirty minutes. Then 290 mg of commercially available 4-cyano-benzenesulfonyl chloride were added and the mixture was stirred at room temperature for additional two hours. Then the solvent was removed in vacuo and the residue was purified by chromatography on silica gel to obtain 307 mg of 4-[6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzonitrile.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][O:9][CH2:8][C@H:7]1[NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[C:15]1([C@H:13]([NH:12][C@H:7]2[C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][O:9][CH2:8]2)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@@H]1CCOC[C@H]1N[C@H](C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3S,4R)-3-[(R)-1-Phenyl-ethylamino]-tetrahydro-pyran-4-carboxylic acid ethyl ester (726 mg, 2.6 mmol) in tetrahydrofuran (6 mL) was treated with 1.0 M sodium hydroxide solution (5.2 mL, 5.2 mmol) and the heterogeneous mixture was stirred at room temperature. After 16 h , the now homogeneous solution was treated with 1.0 M hydrochloric acid (5.2 mL, 5.2 mmol) and concentrated in vacuo. The residue was dissolved in water and lyophilized to provide the product, along with sodium chloride, as a fluffy white solid (943 mg, quantitative), used without further purification. 1H NMR (300 mHz, CDCl3) δ7.41 (m, 5H), 4.09 (q, J=6.6 Hz, 1H), 3.98 (dd, J=11.7, 4.0 Hz, 1H), 3.77 (m, 1H), 3.33 (m, 1H), 3.08 (m, 2H), 2.37 (m, 1H), 2.19 (m, 1H), 1.79 (m, 1H), 1.61 (d, J=6.6 Hz, 3H), ESI MS: (M+H)+=250.3 (100%).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:7]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH3:1][S:2][CH:3]([C:7]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])[C:4]([O:6][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)cc1C(SC)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1C(SC)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 83 %

Procedure:
Ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (4.80 g, 17.9 mmol), ethanol (30 mL) and 10% aqueous solution of sodium hydroxide (20 mL) were mixed and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured in ice water and made acidic with concentrated hydrochloric acid, which was then extracted with ethyl acetate. The extracte was washed with water, dried over anhydrous sodium sulfate, and then concentrated to afford 4.00 g of crude 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic acid as yellow crystals (this compound was used for next reaction without further purification). Next, 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic acid (4.00 g, 16.4 mmol) and N,N-dimethylformamide (50 mL) were mixed and, after anhydrous potassium carbonate (3.71 g, 26.8 mmol) and benzyl bromide (3.06 g, 17.9 mmol) were added at room temperature under stirring, the mixture was stirred for 5 hours. The reaction mixture was poured in ice water and extracted with ether. The extracted solution was washed with water and brine, and then dried over anhydrous sodium sulfate. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate n-hexane:ethyl acetate=6:1 v/v) to afford 4.50 g (76%) of the title compound as a light brown oil.