Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15](OCC)=[O:16])=[C:7]2[OH:20].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:12])([CH3:13])[C:9](=[O:14])[C:8]([C:15]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:16])=[C:7]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A mixture of ethyl 8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.320 g, 0.803 mmol), glycine tert-butyl ester hydrochloride (0.175 g, 1.04 mmol), DIEA (0.280 mL, 1.61 mmol), and 1,4-dioxane (12 mL) were heated at 120° C. for 2 hours in a sealed vessel. The mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with water (30 mL) and then with brine (50 mL), dried over MgSO4, and concentrated and dried in vacuo. The residue was purified by flash column chromatography (silica, 0-50% DCM in hexane) to give 1,1-dimethylethyl N-((8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.214 g). MS m/e=378 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.C(N(CC)CC)C.Cl.Cl.[F:17][C:18]1[CH:19]=[C:20]([C:34]([N:36]2[CH2:45][C:44]3[CH:43]=[N:42][N:41]([CH3:46])[C:40]=3[NH:39][C:38]3[CH:47]=[CH:48][CH:49]=[CH:50][C:37]2=3)=[O:35])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([C:34]([N:36]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:46])[C:40]=4[NH:39][C:38]4[CH:47]=[CH:48][CH:49]=[CH:50][C:37]3=4)=[O:35])=[CH:19][C:18]=2[F:17])[CH2:29][CH2:30]1
Reactant: CC(C)(C)CC=O
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3-Dimethylbutyraldehyde (120 mg, 1.20 mmol) and triethylamine (to pH9) were added to a solution of [3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone dihydrochloride from Example E49 (585 mg, 1.09 mmol) in methanol/acetic acid (99:1, v/v, 20 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (103 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield (4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone, which was lyophilised from aqueous trifluoroacetic acid to give a white solid identified as the title compound (700 mg, 83%).
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.II.[O:25]=O>[Fe](Cl)(Cl)Cl>[P:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:25]
Reactant: O=O
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: Cl[Fe](Cl)Cl
Agent: II
Product: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Reaction time: 2.5 h

Procedure:
To a one-liter, stainless steel Parr autoclave vessel equipped for agitation, heating/cooling, and gas pressurization were charged 710 grams (2.29 moles) of triphenyl phosphite, 1.78 grams (0.0070 mole; 0.31 mole %) of iodine, and 2.34 grams (0.0144 mole; 0.63 mole %) of anhydrous iron (III) chloride. The mixture was heated to 115°-120° C. with efficient agitation and pressurized with oxygen at 55 psig. These conditions were maintained by applying sufficient cooling to control the accompanying exotherm which subsided after about 2.5 hours. The oxygenation was continued until no oxygen pressure drop was observed when the reaction vessel was isolated from the outside pressure line. The total reaction time was 5 hours. When the reaction vessel was vented, there was obtained 747 grams of triphenyl phosphate, an amber liquid that solidified upon cooling to room temperature. Gas chromatography showed the absence of triphenyl phosphite, thus demonstrating that the conversion of the phosphite to the phosphate was quantitative.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:23]([O-:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSCC[C@H](N)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CSCC[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. A solution prepared by dissolving 935 mg (2 mmol) of butyltriphenylphosphonium methionine salt in 15 mL of acetonitrile was dropped to the solution, and then the mixture was stirred for 50 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-methionine was obtained. An isolation amount and an isolation yield were 441.5 mg and 82%, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])=[O:7]
Reactant: CCNCC
Reactant: COc1ccc(C(=O)O)c(OC)c1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(OC)cc1OC
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 50.0 g (0.27 mol) of 2,4-dimethoxybenzoic acid in 60 ml (98.0 g, 0.82 mol) of thionyl chloride was heated under reflux for three hours, then cooled, and the excess thionyl chloride distilled off. The resulting 2,4-dimethoxybenzoyl chloride was dissolved in 150 ml of MDC and the solution treated with a solution of 68 ml (48 g, 0.66 mol) of diethylamine in 500 ml of MDC, cooled to 0° C. When addition was complete the mixture was stirred for fifteen hours at ambient temperature, then washed with saturated sodium bicarbonate, water and brine and taken to dryness and the residue distilled in vacuo to give 44.78 g (69%) of 2,4-dimethoxy-N,N-diethylbenzamide, b.p. 155°-163° C./0.4 mm.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(N(C(C)C)CC)(C)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>ClCCl.CO.CCOCC>[C:16]([NH:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[C@H](N)CO
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of (S)-(+)-2-aminobutan-1-ol (10 g, 112.18 mmol) in dichloromethane (DCM, 250 ml) under an argon atmosphere at room temperature, was added diisopropylethylamine (DIEA, 19.4 ml, 112.18 mmol) followed by trityl chloride (31.2 g, 112.18 mmol). The reaction mixture was stirred at this temperature for 48 h, when TLC (hexane:ether:MeOH; 55:40:5) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The organic solution was washed with water (2×), dried over sodium sulphate. The solvent was removed to afford (S)-2-(trityl-amino)-butan-1-ol as a light yellow oil;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[F:17])=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Fc1ccccc1-c1nnc2ccc(Cl)nn12
Reaction time: 0.67 h

Procedure:
6-Chloro-3-hydrazinopyridazine (6.9 mmol) was suspended in dioxane (45 mL) with triethylamine (1.1 equiv), and the acyl chloride of 2-fluorobenzoic acid (1.1 equiv) in dioxane (10 ml) was added dropwise over 5-10 min at room temperature. The reaction mixture was stirred at the same temperature for 30-50 min (monitored by TLC), and then the dioxane was removed by rotary evaporation. The residue was refluxed in phosphorus oxychloride (40 ml) for 3-4 hours, and then the solvent was evaporated. 6-Chloro-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine was obtained by washing the residue several times with ethyl acetate followed by filtration then adding ice-cold water (50 ml) to the residue. The aqueous layer was neutralized to pH 7 with saturated aqueous sodium hydrogen carbonate, and the resulting solid was collected by filtration, washed twice with water and then with hexane, and dried under vacuum at 50° C. 1H NMR (400 MHz, Me2SO-d6): 8.57 (d, 1H, pyridazine, J=9.3 Hz), 7.85-7.89 (td, 1H, Ph, J=1.6 Hz and 7.4 Hz), 7.68-7.72 (m, 1H, Ph), 7.58 (d, 1H, pyridazine, J=9.4 Hz), 7.45-7.53 (m, 2H, Ph). FABMS (M+H) calculated for C11H6ClFN4.H was 249.0337. found 249.0339.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[N:49]2[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:37][CH:36]=1>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][C:38]4[CH:37]=[CH:36][C:35]([F:34])=[CH:57][CH:56]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 47.3 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt)(0.72 g, 1.55 mmol.) and 4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.88 g, 1.52 mmol) to give the title compound: Rf=0.26 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH2:13][O:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]>C(O)C.[Ni]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C2=COCCC2)cc1
Agent: [Ni]
Solvent: CCO
Product: CCCc1ccc(C2CCCOC2)cc1

Procedure:
10 g of 3-p-propylphenyl-4,5-dihydro-6H-pyran (obtainable by hydrolysis of 3-bromotetrahydropyran to give 3-hydroxytetrahydropyran, reaction with p-propylphenyl magnesium bromide to give 3-p-propylphenyl-3-hydroxy-tetrahydropyran followed by dehydration) are dissolved in 100 ml of ethanol and hydrogenated to standstill on 2 g of Raney nickel at 20° under 3 atmospheres. After decantation and evaporation, 3-p-propylphenyltetrahydropyran is obtained.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([CH:42]3CCCCC3)=[N:38]OC=2C)=NC=1>>[CH:37]([NH:38][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:42])[CH3:36]
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(C3CCOCC3)noc2C)nc1
Product: Cc1onc(C2CCOCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 74 %

Procedure:
As described for example 31e, 6-[5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.3 mol), instead of 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester was converted, to the title compound (80 mg, 74%) which was obtained as a white solid after purification by chromatography (silica, 30 to 70% ethyl acetate in heptane). MS: m/e=360.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH2:7][NH2:8])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.[BH4-].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1)[CH2:7][NH:8][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH3:2]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)N[C@H](CN)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N[C@H](CNCc1ccc(OC)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Crude (S)-[2-amino-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester from above is dissolved in anhydrous EtOH (100 mL). p-Anisaldehyde (2.07 g, 15.2 mmol) is added into the solution and stirred at room temperature for 5 h before the addition of NaBH4 (0.82 g, 21.8 mmol) at 0° C. The mixture is then warmed up to room temperature and stirred for 14 hr. After the solvent is removed under vacuum, the residue is treated with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (3×150 mL). The combined organic layer is washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated to provide the crude (S)-[2-(4-methoxy-benzylamino)-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester as colorless oil (˜6.0 g) which is used directly for next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:27]=2)[S:13]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])(=[O:14])=[O:15])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(N(Cc2cccc(OC3CCCCO3)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CCc1ccc(N(Cc2cccc(OC3CCCCO3)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
To a solution of 3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid methyl ester (0.252 g, 0.46 mmol) in methanol was added palladium black (catalytic amount) and ammonium formate (0.289 g, 4.58 mmol). The reaction mixture was stirred at 60° C. for 24 hr. Additional palladium black (catalytic amount) and ammonium formate (0.289 g, 4.58 mmol) were added and the reaction mixture was stirred at 60° C. for 24 hr. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with water and saturated aqueous sodium bicarbonate. The aqueous solution was washed with methylene chloride. The organic layer was concentrated to afford 0.172 g of the title compound of Step A. 1H NMR (CDCl3) δ 7.10–7.05 (m, 1H), 7.00–6.90 (m, 4H), 6.89–6.80 (m, 4H), 6.75–6.70 (m, 1H), 5.27–5.25 (m, 1H), 4.80–4.70 (m, 2H), 3.85–3.75 (m, 1H), 3.60 (s, 3H), 3.55–3.50 (m, 1H), 2.82 (t, 2H, J=7.6 Hz), 2.53 (t, 2H, J=6.8 Hz), 2.43 (s, 6H), 2.26 (s, 3H), 2.00–1.90 (m, 1H), 1.85–1.75 (m, 2H) 1.65–1.50 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[CH2:12]1[O:14][CH:13]1[CH2:15][CH2:16][CH:17]1[O:19][CH2:18]1>O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:18][CH:17]2[O:19][CH:13]([CH2:12][OH:14])[CH2:15][CH2:16]2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: C(CC1CO1)C1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OCC(COCC2CCC(CO)O2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
46.3 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (0.35 mol) (Aldrich) is cooled to 0° in an ice bath and under a nitrogen atmosphere 2.1 g of sodium hydride (0.088 mol) (washed with hexane to remove the mineral oil) is slowly added to the rapidly stirred mixture. The addition of the sodium hydride is made at such a rate that the temperature remains below 20°. After the addition of the NaH has been completed the mixture is allowed to stir for 1/2 hour and slowly warmed to room temperature. Slowly, and with stirring 10.0 g of 1,5-hexadiene diepoxide (0.088 mol) is added to the mixture. After the addition of the diepoxide has been completed the reaction mixture is heated at reflux for 16 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with two 200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the dark brown residue then vacuum distilled through a 10 cm vigreux distilling column. The fraction boiling at 135°-137° @ 0.3 mm is collected yielding 12.6 g (58%) of the above compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[C:7]([I:12])=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)nc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
3.85 g (12.3 mM) of silver sulfate are added, with stirring and at room temperature, to a solution of 2 g (12.3 mM) of 5-amino-2-(trifluoromethyl)pyridine in 100 ml of ethanol. 3.13 g of iodine are then added and the reaction mixture is stirred at room temperature for 24 hours. The solid in suspension in the medium is removed by filtration and the filtrate is concentrated under reduced pressure. The evaporation residue is taken up in 200 ml of dichloromethane and washed with 5% sodium hydroxide solution, and then with water and dried over magnesium sulfate. The solution obtained is concentrated under reduced pressure and 3.42 g of the expected compound are thus obtained in the form of a pink solid (yield=96%).
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.CN(C)P(=O)([N:26]([CH3:28])[CH3:27])N(C)C>O>[CH3:27][N:26]([CH3:28])[C:11]1[C:10]2[C:9](=[O:19])[C:8]3[C:17](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O
Product: CN(C)c1cccc2c1C(=O)c1ccccc1C2=O
Yield: 92.4 %

Procedure:
25.3 parts of 1-nitroanthraquinone and 227 parts of hexamethylphosphoric triamide are heated in an agitator flask for 4 hours to 180° C and for 11/2 hours to 210° C. After it has been cooled, the reaction mixture is poured into 1000 parts of water. The precipitated product is collected by filtration, washed with water and dried, to yield 23.2 parts (=92.4% of theory) of 1-dimethylaminoanthraquinone.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[S:17][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:28]([O:32][C:33](=[O:50])[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1)([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([O:32][C:33]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[S:17][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:50])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1NC(=O)OC(C)(C)C)n2CC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
A solution (0.15 M) of methyl 5-bromo-4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (from Step 2) in dioxane was treated with tert-butyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.5 eq.) and 2 N Na2CO3 solution (6 eq.) and degassed. PdCl2(PPh3)2 (0.2 eq.) was added and the suspension refluxed for 30 mins. After cooling, EtOAc was added and the solution was washed with water, brine, dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash chromatography (PE:EtOAc, 95:5) to afford the title compound (89%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 8.00 (s, 1H), 7.73 (m, 2H), 7.47-7.43 (t, J 8.6, 1H), 7.27-7.23 (m, 2H), 4.73-4.49 (dd, J 20, 2H), 3.82 (s, 3H), 2.17-2.11 (m, 1H), 1.82-1.21 (m, 10H), 1.37 (s, 9H), 1.28 (s, 9H). MS (ES+) m/z: 569 [M+H]+.