Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:31][C:32]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=1[NH2:34]>>[CH3:31][C:32]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=1[NH:34][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 103.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 2,5-dimethylaniline (0.042 g, 0.35 mmol), the title compound (0.118 g, 99%) was obtained.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[C@@H:29]1[O:46][CH2:45][C@@H:40]([O:41][C:42](=[O:44])[CH3:43])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]1[O:31][C:32](=[O:34])[CH3:33])(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:1][C:2]1[N:3]([C@@H:45]2[O:46][CH2:29][C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:40]2[O:41][C:42](=[O:44])[CH3:43])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 56 %

Procedure:
2-Bromo-5,6-dichlorobenzimidazole (4.0 g, 15 mmol), N,O-bis(trimethylsiyl)acetamide (Aldrich, 3.7 mL, 15 mmol), and 1,2-dichloroethane (Aldrich Sure Seal, 75 mL) were combined and refluxed under nitrogen for 0.5 h. The solution was cooled to room temperature and trimethylsilyl triflate (Aldrich, 3.2 ml, 16 mmol) was added. Immediately, 4.8 g (15 mmol) solid 1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose 1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution was stirred under nitrogen at reflux for 0.5 h, then poured into 7% aqueous sodium bicarbonate and extracted with dichloromethane. The organic layers was dried with magnesium sulfate (anhyd.), filtered, and evaporated. The crude residue was purified on a silica gel column (5×20 cm, 230-400 mesh) with CH2Cl2 to give 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazole which was fractionated in two parts based on elution. The faster product fraction was impure (1.9 g) and purified by a second column to give 1.4 g (2.7 mmol); the slower product fraction was (3.0 g, 5.7 mmol) for a total yield of 56%; m.p. 100-110° C.; 1H NMR (DMSO-d6) δ 8.39 (s, 1H), 7.91 (s, 1H), 5.95-5.92 (d, 1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6 Hz), 5.67 (bs, 2H), 4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz), 4.00-3.95 (overlapping dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:34]=[C:35]([NH:39][C:40]3[C:45]([N+:46]([O-:48])=[O:47])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([NH:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:34]=[C:35]([NH:39][C:40]3[C:45]([N+:46]([O-:48])=[O:47])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=1)=[O:11]
Reactant: O=C(O)C=Cc1ccccn1
Reactant: Nc1cccc(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccn1)Nc1cccc(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To an ice cooled suspension of 3-(2-pyridyl)acrylic acid (1.07 g) in dry methylene chloride (80 ml) was added triethylamine (1.46 g) and pivaloyl chloride (0.87 g) and the mixture was stirred for 2 hours. After the clear reaction mixture was obtained, 2-[3-(3-aminophenyl)phenylamino]-3-nitropyridine (2.0 g) was added thereto and stirred under reflux overnight. The reaction was chromatographed on silica gel (chloroform-methanol 50:1 as an eluent) to give 2-[3-[3-[(E)-3-(2-pyridyl)acryloylamino]phenyl]phenylamino]-3-nitropyridine as an orange crystal (2.85 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].ClC1C=CC(C(NC2C=CC=C(C3OCCO3)C=2)=O)=CC=1.N1CCC(C(OC)=O)C1.C([O:43][C:44]([CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([NH:59]C(=O)C3C=CC(Cl)=CC=3)[CH:54]=2)[CH2:48]C1)=[O:45])C>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]([NH:59][C:55]2[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=2)[CH2:52][N:49]2[CH2:50][CH2:51][CH:46]([C:44]([OH:43])=[O:45])[CH2:48]2)=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(C(=O)Cl)c1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Agent: COC(=O)C1CCNC1
Agent: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCC(C(=O)O)C3)c2)c1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 5-methylnicotinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and methyl pyrrolidine-3-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0. 45 min; [M+H]+=340.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:19])[NH:13][CH:14]=[C:15]([Cl:18])[C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6].Br[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24](C(OC(C)(C)C)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:19])[N:13]([CH2:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[CH:14]=[C:15]([Cl:18])[C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)c(Cl)c[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)c(Cl)cn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-[(4,5-dichloro-2-oxo-1,2-dihydropyridin-3-yl)oxy]benzonitrile (49 mg, 0.155 mmol) in DMF (1 mL) was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (48.5 mg, 0.155 mmol) and potassium carbonate (21.46 mg, 0.155 mmol) and the mixture heated at 55° C. for 30 minutes. After this time, the reaction mixture was allowed to cool to room temperature and the mixture was filtered through a Gelma Acrodisc. The filtrate was purified on Gilson LC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) eluting with a gradient of 20-95% ACN/water (0.5% TFA). The desired fractions were combined and evaporated in vacuo. This residue was dissolved in TFA (3 mL) and allowed to stand at room temperature for 15 minutes and then the solvent was evaporated in vacuo to give a white solid. This solid was suspended in ACN (10 mL) and the solvent removed in vacuo to give the title compound. 1H NMR (DMSO-d6) δ=8.52 (d, 1H, J=3.8 Hz), 8.41 (s, 1H), 8.19 (d, 1H, J=7.9 Hz), 7.74 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.19 (dd, 1H, J=4 and 8.9 Hz) and 5.49 (s, 2H) ppm. HRMS (M+1): 445.9991.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccn1
Yield: 48 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. Yield: 48% of theory, C29H31N7O5 (557.6) Rf value: 0.62 (silica gel; dichloromethane/methanol=9:1) ##EQU72##
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:13])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(O)nc1C
Product: CCOC(=O)c1ccc(Cl)nc1C
Temperature: 150 °C

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
1,4-Difluoro-2-nitrobenzene (2.63 g, 16.53 mmol) was dissolved in EtOH (9 mL) and Methylamine 40% in Water (9 mL) was added dropwise at 0° C. and the mixture was warming up to RT overnight. 75 mL of water was added to the reaction mixture and the orange solid was filtered and washed with water (2*10 ml) to afford 2.78 g of 4-fluoro-N-methyl-2-nitrobenzenamine (Yield: 99%) as an orange crystalline solid.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>C(O)C>[C:18]([CH:19]=[CH:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=CC(=O)c2ccccc2)cc1

Procedure:
7.1 Parts of ethyl (4-formylphenoxy)-2,2-dimethylacetate described in U.S. Pat. No. 3,842,120 and 4.7 parts of acetophenone in 10 parts by volume of ethanol containing 0.01 part of sodium ethyl are reacted for 2 hours. This reaction mixture is quenched with 100 parts of cold water and extracted with ether. The ether extracts are dried over magnesium sulfate. Filtration of the magnesium sulfate, removal of the ether by evaporation at reduced pressure, and column chromatography on silica gel provides ethyl 2-[4-(2-benzoylethenyl)phenoxy]-2,2-dimethylacetate, melting at 68° to 70° C. This compound has the following structural formula ##STR5##
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[C:4]=1[F:17])#[N:2].[ClH:18]>CO.CCOCC.[Pd]>[ClH:18].[F:17][C:4]1[C:5]([F:16])=[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:7]([F:10])=[C:8]([F:9])[C:3]=1[CH2:1][NH2:2]
Reactant: CS(=O)(=O)Nc1c(F)c(F)c(C#N)c(F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Nc1c(F)c(F)c(CN)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
4-cyano-2,3,5,6-tetrafluoro-1-methanesulfonylaminobenzene (11 mg) prepared in Step 1 was dissolved in methanol (5 ml) and to the solution were added a catalytic amount of 10% palladium/carbon and concentrated hydrochloric acid (300 μl), followed by stirring at room temperature under hydrogen gas atmosphere for 1 hour. The resulting mixture was diluted in ether, filtered through celite, concentrated under reduced pressure, and then washed with ethyl acetate to yield 2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzylamine hydrochloride (7.0 mg, 59%).
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([O:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:31][CH3:32])[C:4]([OH:33])=[O:3])=[CH:8][CH:9]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCCOc2ccc(-c3ccccc3)cc2)cc1)OC
Agent: [Li+]
Agent: [OH-]
Product: COC(Cc1ccc(OCCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic acid ethyl ester from Step C under the standard Hydrolysis procedure C. (LiOH). 1H-NMR (200.15 MHz, CDCl3): 7.57–7.49 (m, 4H); 7.45–7.37 (m, 2H); 7.32–7.11 (m, 3H); 6.97 (d, 2H, J=8.9); 6.84 (d, 2H, J=8.9); 4.11–3.93 (m, 5H); 3.40 (s, 3H); 3.10 (dd, 1H, J=14.0, 4.3); 2.96 (dd, 1H, J=14.5, 7.0); 1.99–1.97 (m, 4H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22)(256 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 32%). MS (ISP) 604.0[(M+H)+]; mp 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:20])[CH:4]2[CH2:19][C:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2.[BH4-].[Na+].[Cl-].[NH4+]>CCO>[Cl:1][C:2]1[C@H:3]([OH:20])[C@H:4]2[CH2:19][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2
Reactant: O=C1C(Cl)=C2c3ccc4[nH]ncc4c3CC23CCC1C3
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O[C@H]1C(Cl)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3

Procedure:
To a stirring suspension of 6-chloro-3,9,10,11-tetrahydro-8,10a -methanoazuleno[2,1-e]indazol-7(8H)-one (305 mg, 1.07 mmol) in EtOH (30 mL) was added sodium borohydride (122 mg, 3.2 mmol) at room temperature. A bright yellow color appeared shortly after this addition and with time the reaction mixture became homogeneous. The reaction mixture was stirred at room temperature for 3 hours after which saturated aqueous ammonium chloride was added in portions until bubbling stopped. The reaction mixture was then diluted with ethyl acetate and washed with water followed by brine. The organic phase was dried over sodium sulfate, filtered through a small pad of silica gel, and then concentrated under vacuum to yield (rac)-(7R,8R,10aS)-6-chloro-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno-[2,1-e]indazol-7-ol as a faintly yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:25]([O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1])(=[O:27])[CH3:26]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
The N-FMOC protected L-Thyroxine (26.3 g, 23.2 mmol) was dissolved in 150 mL THF, 3.28 mL (34.8 mmol) of acetic anhydride added, 283 mg (2.32 mmol) of 4-dimethylaminopyridine added, and reaction stirred under N2 for 45 minutes, then poured into 400 mL H2O and extracted with CHCl3 (3×400 mL). The CHCl3 extracts were combined, dried over Na2SO4, and solvent removed in vacuo. The residue was then purified by silica gel column chromatography, eluting with CH2Cl2 /MeOH/HOAc (90/10/0.4, v/v), to yield 21.95 g (91%) of the desired O-acetyl thyroxine as a beige solid; 1H NMR (300 MHz, DMSO-D6) d 7.12-7.91 (m, 12H), 4.07-4.31 (m, 4H), 3.07-3.19 (m, 1H), 2.82 (t, 1H), 2.29-2.40 (m, 3H); mass spec (FAB) (M+H)+ 1042.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1.B(F)(F)F.CCOCC.N(OC(C)(C)C)=O.[Na].[OH-].[Na+]>C1COCC1.O>[CH2:7]([C:5]1[N:6]=[CH:2][S:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1sc(N)nc1CC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1scnc1CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To a 0° C. solution of ethyl 2-amino-4-ethyl-1,3-thiazole-5-carboxylate (4.0 g, 18.2 mmol) in anhydrous THF (65 mL) was added boron trifluoride diethyl etherate (3.2 mL, 25.5 mmol). After 15 minutes of stirring at 0° C. was added tert-butyl nitrite (10 mL, 84 mmol). The mixture was stirred at 0° C. for 3 hours before a solution of sodium hypophosphonate (6.4 g, 73 mmol) in water (20 mL) was added. The mixture was stirred at 0° C. for 2 hours and at room temperature overnight. The solution was basified to pH 8-9 with 5 N NaOH and was extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 4-ethyl-1,3-thiazole-5-carboxylate (3.19 g, 85% yield). The product was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH3:17].Cl>CN(C=O)C>[CH2:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(=O)OCC
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 107.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 315 mmol, 1.05 equiv) in DMF (300 mL) at 23° C. was added a solution of diethyl malonate (45.5 mL, 300 mmol, 1 equiv) in DMF (100 mL) via cannula over the course of 10 min. The addition caused a mild exotherm and H2 gas evolution was observed, cooling was not necessary. Following the addition, the reaction was stirred for 45 min at 23° C. then treated with 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction was stirred at 23° C. for 25 min, then heated to 65° C. for 3 h, then stirred at 23° C. overnight. The reaction mixture was added to 1.0 N HCl (1 L) then extracted with diethyl ether (700 mL). The ether extracts were washed with H2O (400 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 65.1 g of product as a clear oil. 13C NMR revealed approximately 4:1 mono:bis-alkylated product. The product diethyl n-propylmalonate was used without further purification: 1H NMR (300 MHz, CDCl3) 4.18 (q, J=6.9 Hz, 4H), 3.32 (t, J=7.8 Hz, 1H), 1.91–1.79 (m, 2H), 1.41–1.25 (m, 2H), 1.25 (t, J=6.9 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (300 MHz, CDCl3) (*denotes signal due to minor product of bis-alkylation)? 169.6, 61.2, 60.9*, 51.8, 34.4*, 30.7, 20.5, 17.3*, 14.4*, 14.0, 13.7.
Reaction SMILES: C(O[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([O:18][C:19]1[C:20]([N+:26]([O-])=O)=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])C.[K+]>C(OCC)C>[CH2:8]([O:7][C:5]([C:4]1[NH:26][C:20]2[C:21]([CH:25]=1)=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:6])[CH3:9]
Reactant: Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Yield: 36.1 %

Procedure:
Under agitation, 26.3 g of oxalic acid diethyl ester and, 15 minutes later, a solution of 21.9 g of 3-benzyloxy-2-nitrotoluene in 30 ml of diethyl ether are added dropwise to a suspension of 9 g of potassium ethanolate in 200 ml of diethyl ether. The reaction mixture is heated for 20 hours under reflux; the thus-separated potassium salt of 3-benzyloxy-2-nitrophenylpyruvic acid ethyl ester is vacuum-filtered and washed with diethyl ether. The salt is then dissolved in a mixture of 200 ml of ethanol and 200 ml of concentrated acetic acid, the solution is combined with 50 g of powdered iron and heated under reflux for 90 minutes. The reaction mixture is allowed to cool, poured into 1 liter of ice water, filtered over kieselguhr, and the kieselguhr washed with diethyl ether. The organic phase is separated and the aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed with saturated sodium carbonate solution, dried, and concentrated under vacuum. The residue is recrystallized from ethanol, thus obtaining 9.6 g of 7-benzyloxyindole-2-carboxylic acid ethyl ester, mp 82°-83° C.