Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1>CCO>[Cl:5][C:6]1[N:11]=[C:10]([S:1][C:2]#[N:3])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(compound known, e.g. WO 2003/032994) Potassium thiocyanate (0.97 g, 10 mM) was added to a solution of 2,4-dichloro-5-nitropyrimidine (1.94 g 10, mM) in EtOH (40 mL) cooled to 0° C. via an ice bath. The solution was stirred at 0° C. for 30 min, then the bath was removed and the resulting suspension allowed to come to RT over 60 min, when water (100 mL) was added. The precipitate was collected via filtration, washed with ice cold water, dissolved with DCM, dried (MgSO4), filtered and evaporated to yield the titled compound (1.7 g). 1H-NMR (300 MHz, CDCl3) δ 9.4 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[C:15]([S:28][CH3:29])[N:16]=[C:17]([NH:18][CH:19]4[CH2:21][CH:20]4[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]=3[N:11]=[N:10]2)[CH:6]([OH:30])[CH:5]1[OH:31].[CH2:32](S)[CH2:33][CH2:34]C>>[CH2:29]([S:28][C:15]1[N:16]=[C:17]([NH:18][CH:19]2[CH2:21][CH:20]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[N:11]=[N:10][N:9]([CH:7]3[CH2:8][CH:4]([CH2:3][CH2:2][OH:1])[CH:5]([OH:31])[CH:6]3[OH:30])[C:13]=2[N:14]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCS
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1
Product: CCCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1

Procedure:
Prepared by the method of Example 4, step (b) using the product of Example 110, step a) and butanethiol then deprotected using the method of Example 1, step (b). Purification (HPLC, Novapak® C18 column, 0.1% aqueous ammonium acetate:acetonitrile, isocratic elution 45% MeCN over 30 minutes) afforded the title compound (210 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.C1C(=O)N([Br:24])C(=O)C1>C1COCC1.CN1C(=O)CCC1>[Br:24][C:14]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:16][CH:15]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2nc(Cl)c3nccn3c2cc1C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)c3ncc(Br)n3c2cc1C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred suspension of 4-chloro-7,8-dimethyl-imidazo[1,2-a]quinoxaline (32.2 g, 0.148 mot) in THF/NMP 2:1 (312 mL) was added NBS (26.3 g, 0.148 mot) in one portion at room temperature. After stirred for 18 h, additional NBS (13.1 g, 0.074 mot) was added and the mixture was stirred for additional 2 h at room temperature. After removal of the THF portion of the organic phase by vacuum evaporation, water was added (520 mL). The precipitate was filtered and the residue was washed with water, diethyl ether and dried to give 35 g of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ=8.54 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 2.20 (6H, s) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:18]O>>[CH3:18][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])c[nH]c1C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of sodium nitrite (714 g, 10.2 mol) in 700 ml of water at 50° C.±5° C. was added over a period of 3 hours a solution of mucobromic acid (48) (700 g, 2.7 mol) in 700 ml of warm ethanol. The reaction was stirred for 15 minutes, cooled to 0° C., and 700 ml of ethanol was added. The resulting orange precipitate was collected by vacuum filtration and dried in vacuo to yield sodium nitromalondialdehyde monohydrate (305 g, 1.9 mol) which was used in the next step without further purification. Glycine ethyl ester (300 g, 2.9 mol) and nitromalondialdehyde monohydrate (305 g, 1.9 mol) were placed in a 12 l round bottom flask and slurried with a mechanical stirrer in 560 ml of methanol and 280 ml of water. Sodium hydroxide (800 g, 20 mol) dissolved in 1.6 l water was added to the solution at a rate which maintained the temperature at 50° C. The reaction was cooled to 0° C. with an ice bath and neutralized to pH 0 with 1.7 1 HCl (conc.) while maintaining the temperature below 10° C. A black precipitate was removed by filtration through Celite and the product was extracted with 20 liters of ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) as a brown solid which was used without further purification. To a solution of 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) dissolved in 180 ml of methanol was added 8 ml of concentrated sulfuric acid. The solution was refluxed for 15 hours, cooled to 0° C. and 90 ml of water was added. The solution was then allowed to stand at -20° C. for 2 days. The resulting light brown crystals were collected by vacuum filtration to yield pure methyl 4-nitropyrrole-2-carboxylate (49) (105 g, 0.62 mol) in 23% overall yield. 1H NMR (DMSO-d6) δ 14.2 (br s, 1H), 7.74 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=1.7 Hz), 3.73 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([OH:26])=O)[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Product: O=C(Nc1nccs1)Nc1ccc(CC(=O)N2CCOCC2)cc1C(=O)C1CCCC1
Yield: 68.2 %

Procedure:
1-[2-Cyclopentanecarbonyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenyl]-3-thiazol-2-yl-urea (151 mg, 68%) was prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)-phenyl]-acetic acid (186 mg, 0.5 mmol) and morpholine (44 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [Cl:1]C1C(C([O-])=O)=NC2C(C=1)=CC=CC=2OC.O[C:18]1[C:27]2[C:22](=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:18]1[C:27]2[C:22](=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=1
Reactant: COC(=O)c1cc(O)c2cccc(OC)c2n1
Reactant: COc1cccc2cc(Cl)c(C(=O)[O-])nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c2cccc(OC)c2n1
Temperature: 80 °C
Yield: 69 %

Procedure:
Methyl 4™chloro-8-methoxyquinoline-2-carboxylate compound of the formula V, R5 =CH3O, R6 =H, R8 =CH3 57.6 g (247 mmol) of methyl 4-hydroxy-8-methoxyquinolinecarboxylate were introduced a little at a time into 113 ml of POCl3 at room temperature to 40° C., and the mixture was heated at 80° C. for 2 hours. The dark reaction mixture was poured onto ice and adjusted to pH 6 with concentrated K2CO3 solution. The precipitate was filtered off with suction and recrystallized from DMF/water. 42.7 g (=69%) of methyl 4-chloro-8-methoxyquinoline-2-carboxylate of melting point 139-141° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12]C(O)=O)=[CH:8][C:7]=1[CH3:16])=[O:5].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[CH:8][C:7]=1[CH3:16])=[O:5]
Reactant: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCC(=O)O
Product: Cc1cc(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
A solution of 62.69 g (0.18 mole) 5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (4)in 550 mL of propionic acid was heated under reflux overnight then poured into water. The solution was extracted three times with diethyl ether. The ether solution was washed successively with NaHCO3, water and brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a tan solid which was recrystallized from methylcyclohexane: mp 96°-98° C.; mass spectrum (Cl--CH4) m/z=282 (M+1); NMR 300 MHz (CDCl3) d 7.5 (s, 1H); 7.35-7.2 (m, 2H); 5.8 (s, 1H ); 3.9 (s, 3H); 2.25 (s, 3H); 1.6 (s, 3H). Anal Calcd for C14H13Cl2NO: C, 59.59; H, 4.64; N, 4.96. Found: C, 59.79; H, 4.39; N, 4.92.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][CH2:48][NH2:49])=[CH:46][C:41]=2[O:40][CH2:39]1>>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][CH2:48][NH:49][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCCc1ccc2c(c1)OCO2
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-benzo[1,3]dioxol-5-yl-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) gave the title compound in 75% yield, m.p. 178-179° C.; MS [(+)ESI, m/z]: 600 [M+H]+
Reaction SMILES: [CH2:1]([N:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[CH:23][CH:22]=1)[C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>>[CH2:1]([N:5]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:35])(=[O:36])[NH:34][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=2[Cl:37])=[CH:25][CH:26]=1)[C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:16])[F:17])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Yield: 29 %

Procedure:
Following the procedure of Example 1, Step I, 1-butyl-3-methyl-1-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3-[2-(trifluoromethyl)phenyl]urea was acylated with 2-chlorobenzoic acid. After work-up, the crude product was purified initially by flash chromatography on silica gel (elution with 2% and then 5% MeOH in CH2Cl2). Further purification by HPLC on a Zorbax C8 Semiprep reversed phase column (70:30 MeCN--H2O, containing 0.1% TFA) provided a 29% yield of the title compound as a stiff, white foam, mp>60° C. (gradual); homogeneous by TLC (95:5 CH2Cl2 --MeOH); FAB-MS m/e 658 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][C@@:8]2([CH3:35])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=3)[C:9]2=[O:34])=[CH:5][CH:4]=1)#[N:2].Cl.Cl.[Br:40][C:41]1[CH:42]=[CH:43][C:44]([C@H:47]([NH2:49])[CH3:48])=[N:45][CH:46]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:40][C:41]1[CH:42]=[CH:43][C:44]([C@H:47]([NH:49][C:22]([C:19]2([NH:18][C:16]([C:13]3[N:12]4[C@@:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:37][CH:36]=5)([CH3:35])[C:9](=[O:34])[N:10]([C:25]5[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=5)[C:11]4=[N:15][CH:14]=3)=[O:17])[CH2:21][CH2:20]2)=[O:24])[CH3:48])=[N:45][CH:46]=1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: C[C@@H](N)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A suspension of 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid, (500 mg, 0.92 mmol), (R)-1-(5-bromo-pyridin-2-yl)-ethylamine dihydrochloride (303 mg, 1.11 mmol) and diisopropylethylamine (0.640 mL, 3.69 mmol) in 4 mL of DMF was stirred at room temperature for 10 min HATU (386 mg, 1.01 mmol) was added, and the clear yellow reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between 75 mL of ethyl acetate and 25 mL of water. The organic phase was washed with 2×25 mL of 5% aqueous NaCl solution and 25 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-3% MeOH in CH2Cl2, to provide 653 mg (98%) of title compound as a yellow foam, m/z 726.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC1CCOC1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCOC1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(tetrahydro-furan-3-ylmethyl)-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 72 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The resulting brown oil was further purification by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless foam (11%). MS (ESI): m/z=553.141 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a stirred solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (0.70 g, 2.2 mmol) in 15 mL of anhydrous THF cooled to 0° C. with an ice bath was added NaH [60% dispersion in mineral oil] (0.13 g, 3.3 mmol). The reaction mixture was stirred for 20 min at 0° C., after which p-toluenesulfonyl chloride (0.47 g, 2.4 mmol) was added. The resulting mixture was stirred at 0° C. for 1.5 hr, after which cold 0.5 M HCl (20 mL) was added. The mixture was partitioned between EtOAc and 0.5 M HCl, after which the organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo to yield a residue that was triturated with 20% CH2Cl2 in hexanes to yield the title compound (0.84 g, 81%) as a light yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (d, J=2.1 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 8.00 (d, J=5.1 Hz, 2H), 7.44 (dd, J=8.7 Hz, 0.6 Hz, 2H), 2.35 (s, 3H); MS ESI (m/z): 477.0/479.0 (M+1)+, calc. 476.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][N:52]([CH3:67])[S:53]([C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([F:65])[CH:63]=2)[N:58]([NH2:66])[CH:57]=1)(=[O:55])=[O:54]>CN(C=O)C>[CH3:51][N:52]([CH3:67])[S:53]([C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([F:65])[CH:63]=2)[N:58]([NH:66][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:57]=1)(=[O:54])=[O:55]
Reactant: CN(C)S(=O)(=O)c1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(S(=O)(=O)N(C)C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 36.1 %

Procedure:
A solution of 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid (116 mg) and HATU (190 mg) in dry DMF is treated with DIPEA (0.09 mL) and stirred at rt for 40 min. 1-Amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide (192 mg) is added and the mixture is stirred at rt for 24 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with 2 N aqueous NaOH, water and brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30% EtOAc/heptane to afford 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide (85 mg, 40%) as a solid. MS: 472 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.68 (s, 6H), 2.79 (s, 3H), 7.25-7.35 (m, 1H), 7.45-7.55 (m, 1H), 7.57-7.80 (m, 3H), 8.20 (d, 1H), 8.35 (s, 1H), 8.47 (s, 2H), 9.28 (s, 1H), 12.40 (s, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][Si:5]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)([CH3:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N:26](OCCC(C)C)=[O:27].C(O)(=O)C>CO>[CH3:4][Si:5]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[N:26][OH:27])[C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1)([CH3:13])[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: CC(=O)Cc1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)C(=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
28 ml of a 30% solution of sodium methanolate in methanol are added at room temperature to 31.6 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propan-2-one in 300 ml of methanol, and 27 ml of isopentyl nitrite are then added dropwise. The reaction mixture is stirred for a further hour and rendered neutral with acetic acid; the solvent is evaporated off in vacuo. 200 ml of ethyl acetate are added to the residue; the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off in vacuo. Recrystallisation from diethyl ether/hexane yields the title product having a melting point of 115-117° C.
Reaction SMILES: CS([Cl:5])(=O)=O.C(N(CC)CC)C.[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:5][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[I:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1ccccc1I
Temperature: 0 °C
Reaction time: 19 h
Yield: 100.7 %

Procedure:
Methanesulfonyl chloride (2.0 ml, 29 mmol) and triethylamine (3.6 ml, 26 mmol) were added to a solution of o-iodobenzyl alcohol (5.0 g, 21 mmol) in methylene chloride (50 ml) cooled to 0° C., and the mixture was stirred at that temperature for 19 hours. A 5% aqueous sodium hydrogencarbonate solution was added, and the resulting mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (5.34 g).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[I-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>O.C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(OCCCCCCO)cc1
Yield: 90.9 %

Procedure:
To a solution of 40 g (1 mole) of sodium hydroxide in 60 ml of water and 400 ml of ethanol were added 122.12 g (1 mole) of 4-hydroxybenzaldehyde, 30 g of sodium iodide and 136.62 g (1 mole) of 1-chloro-6-hydroxyhexane. The mixture was heated at reflux for 24 hours under a nitrogen atmosphere. After cooling, the mixture was filtered and the solvent was removed under reduced pressure. Water (400 ml) was added to the residue and the mixture was extracted twice with 400 ml of ethyl acetate. The ethyl acetate layers were extracted twice with 200 ml of 5% aq. sodium hydroxide, and once with 200 ml of brine, dried over magnesium sulfate, and the solvent was evaporated. A brown oil (202 g, 91%) was obtained, which crystallized slowly.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[C:21]([O-:24])(=[O:23])[CH3:22].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([O:24][CH2:2][C@@H:3]1[CH2:4][C@H:5]([CH2:11][C:12](=[O:13])[N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[O:6][C:7]([CH3:10])([CH3:9])[O:8]1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)N(C(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC(=O)OC[C@@H]1C[C@H](CC(=O)N(C(C)C)C(C)C)OC(C)(C)O1

Procedure:
Heated the reaction mixture of 250 grams of 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-diisopropylacetamide, 225 grams of sodium acetate and 290 grams of tetra butyl ammonium bromide to 110-115° C. Stirred the reaction for 12 hours at 110-115° C. Diluted the reaction mixture with petroleum ether and filtered the byproduct. Organic layer washed with water. Distilled the solvent completely under reduced pressure. Isolated the material in petroleum ether. Dried the material at 40-45° C. to get the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](O)([C:21]([F:24])([F:23])[F:22])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:20].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:20])[C:21]([F:23])([F:24])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C(C)C)cc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccc(C(C)C)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-1-(4-isopropylphenyl)-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).