Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].ClC1C=CC=CC=1.C(O)(=[O:21])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:21])=[O:10]
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a flask equipped with a stirrer, condenser and oxygen inlet tube were added mesitaldehyde (14.8 g, 0.10 mol), 25 mL of chlorobenzene and a solution of 10 mg of cobalt (II) acetate in 1 mL of acetic acid. Oxygen was bubbled in while the solution was vigorously stirred. The reaction temperature rose to 88° in 20 min and then returned to room temperature after one hour. The reaction mixture was mixed with 60 mL of methylene chloride, and 100 mL of water was added. Aqueous potassium hydroxide (40%) was added dropwise until the pH reached 8. The aqueous layer was separated, washed successively with 50 mL of methylene chloride and 50 mL of petroleum ether, and acidified with concentrated hydrochloric acid to a pH of 2. The white solid product was collected by filtration, washed with water and air dried to give 9.82 g (60% yield) of mesitoic acid: mp 153.5°-155.5° C.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].[BrH:28]>O>[Br:28][CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:20][CH2:19][C@H:18]([C@H:15]2[CH2:14][CH2:13][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCO)CC2)CC1
Reactant: Br
Solvent: O
Solvent: Cc1ccccc1C
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCBr)CC2)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To 350 ml of xylene were added 341 g (1280 mmol) of the crude 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propanol obtained by the procedures described above and 881 g (5120 mmol) of 47% hydrobromic acid, water was removed by azeotropic distillation, and then the mixture was stirred at 150° C. for 2 hours. To the reaction mixture was added 1.0 l of toluene, and it was washed with 300 ml of saturated aqueous sodium carbonate solution twice and with 400 ml of water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 156 g of a crude 1-bromo-3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propane.
Reaction SMILES: [B-](F)(F)(F)F.[N:6]#[O+:7].[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].N1C=CC=CC=1>C(#N)C>[N:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=NN1CCC[C@H]1C(=O)O

Procedure:
To a cooled suspension of 28.2 g of nitrosyl tetrafluoroborate in 300 ml of dry acetonitrile there is added, with vigorous stirring, over the course of 10 minutes, 18.4 g of L-proline, followed by a solution of 19 g of pyridine in 50 ml of acetonitrile during 15 minutes. The stirring is continued for an hour and the reaction mixture is then concentrated to dryness under reduced pressure. The residue is extracted with 3×200 ml of ethyl acetate, the ethyl acetate extracts are combined, washed twice with saturated sodium chloride solution that has been made slightly acidic with concentrated hydrochloric acid. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated to dryness at room temperature under reduced pressure. The product, N-nitroso-L-proline melts at 108°-109° (dec.) after crystallization from a mixture of ether and petroleum ether (30°-60°).
Reaction SMILES: [F:1][C:2]([P:8]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(F)F)([F:7])[C:3]([F:6])([F:5])[F:4].C(=O)=[O:26].[PH5].[P:29]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])([C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38])[C:30]([C:33]([F:36])([F:35])[F:34])([F:32])[F:31].P(O)(C(C(F)(F)F)(F)F)(C(C(F)(F)F)(F)F)=O>>[F:1][C:2]([P:8](=[O:26])([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])([F:7])[C:3]([F:6])([F:5])[F:4].[P:29]([C:30]([C:33]([F:34])([F:35])[F:36])([F:31])[F:32])([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])[C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38]
Reactant: O=C=O
Reactant: FC(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [PH5]
Product: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 6 h

Procedure:
12.01 g (28.0 mmol) of tris(pentafluoroethyl)difluorophosphorane, (C2F5)3PF2, are initially introduced in a 100 ml glass round-bottomed flask and warmed (120° C. oil-bath temperature). A cooled (−30° C. to −35° C.) intensive reflux condenser is connected downstream of the flask. A 250 ml glass round-bottomed flask containing dry ice is connected via a T-piece so that gaseous CO2 is forced through the phosphorane liquid. The liquid is stirred at 120° C. for 6 h. In this time, a total of about 400 g (9 mol) of CO2 are bubbled through the hot liquid. After 6 h, the condenser temperature is warmed to −5° C. The clear and colourless liquid remaining (4.53 g) consists of (C2F5)3PF2 (49%), (C2F5)3P═O (49%) and (C2F5)2P(O)OH (2%). Tris(pentafluoroethyl)phosphine oxide, (C2F5)3P═O, is isolated from the reaction mixture by distillation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1.[N+:41]([O-])([OH:43])=[O:42].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1)[N+:41]([O-:43])=[O:42]
Reactant: O=C(NCCCCCCCCCCCO)c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=C(NCCCCCCCCCCCO[N+](=O)[O-])c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Reaction time: 6 h
Yield: 57 %

Procedure:
0.66 g of N-(11-hydroxy-1-undecanyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide were dissolved in 15 ml of methylene chloride and to the solution was added dropwise under ice-cooling a mixed solution of 0.2 ml of fuming nitric acid and 0.5 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 0.41 g (57%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[N:8]=[CH:7][NH:6][C:5]=1[C:9]#[N:10])(=O)[CH3:2].O.[NH2:12][NH2:13]>C(O)C>[NH2:10][C:9]1[N:13]=[N:12][C:1]([CH3:2])=[C:4]2[N:8]=[CH:7][NH:6][C:5]=12
Reactant: NN
Reactant: CC(=O)c1nc[nH]c1C#N
Solvent: O
Solvent: CCO
Product: Cc1nnc(N)c2[nH]cnc12
Temperature: 100 °C

Procedure:
A mixture of 2.00 g 5-acetyl-3H-imidazole-4-carbonitrile and 4.00 ml hydrazine hydrate in 50 ml of ethanol is heated to 100° C., until the reaction is complete according to HPLC-MS. After cooling to ambient temperature the reaction mixture is evaporated down, stirred with 20 ml of cold ethanol and suction filtered. The filter cake is washed with diethyl ether and dried.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2Cl)=[CH:6][CH:5]=1.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2[N:33]2[CH2:34][CH2:35][C@@H:31]([F:30])[CH2:32]2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1N1CC[C@@H](F)C1

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(4-trifluoromethoxy-phenyl)-2-chloro-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid amide (177 mg, 0.40 mmol), (R)-3-fluoro-pyrrolidine×HCl (56 mg, 0.44 mmol), DIPEA (0.55 mL, 3.2 mmol) and MeCN (5 mL).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][N:7]=1.[Cl:17][C:18]1[C:19]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C@@H:34]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:35](OC)=[O:36])=[C:27]3[CH:26]=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C@@H:34]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:35]([NH:5][C:6]4[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][N:7]=4)=[O:36])=[C:27]3[CH:26]=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: CN(C)C(=O)c1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C(=O)N(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Trimethylaluminium (2M in hexane, 0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (CAS no. 827588-33-0) (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (Intermediate L1) (256 mg, 0.65 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. 2M Trimethylaluminium in hexane (0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. The residue from the above evaporation was dissolved in toluene (6 mL) and added dropwise. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12](Br)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Brc1nccc2c1ccn2Cc1ccccc1
Solvent: CCO
Product: c1ccc(Cn2ccc3c(N4CCNCC4)nccc32)cc1

Procedure:
A solution of 4.5 g of 1-benzyl-4-bromo-1H-pyrrolo[3,2-c]pyridine in 25 ml of anhydrous ethanol and 8 g of piperazine are stirred at 120° C. for 15 hours under an inert atmosphere, then brought to ambient temperature and concentrated under reduced pressure. The residue is taken up in 200 ml of dichloromethane and washed with water. The organic phase is treated in conventional manner and then concentrated, enabling the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[N:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]([C:20](Cl)=[O:21])[C@@H:8]([CH3:23])[CH2:7]1)[CH3:2].[F:32][C:33]([F:37])([F:36])[CH2:34][OH:35].[H-].[Na+]>O1CCOCC1>[F:32][C:33]([F:37])([F:36])[CH2:34][O:35][C:20]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C@H:6]([N:5]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:31])[CH2:7][C@@H:8]1[CH3:23])=[O:21]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)Cl)c2cc(OC)c(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCC(F)(F)F)c2cc(OC)c(OC)cc21
Yield: 156 %

Procedure:
A solution of benzyl-(1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 107A) (24 mg, 0.054 mmol), 2,2,2-trifluoroethanol (0.10 mL, 1.4 mmol), and sodium hydride (56 mg, 60% dispersion in mineral oil, 1.4 mmol) in anhydrous dioxane (1 mL) was stirred at room temperature overnight. The reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with 10 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 43 mg of an oil. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the desired final product (15 mg, 58%): MS m/z 510 (M+), 528 (M+ +18); 1H NMR (CDCl3) δ 6.99 (C8, s, 1H), 6.44 (C5, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12].F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:54][C@H:55]([CH2:58][CH2:59][CH2:60][CH3:61])[CH2:56][OH:57]>CN(C=O)C>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:54][C@H:55]([CH2:58][CH2:59][CH2:60][CH3:61])[CH2:56][OH:57])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)c(F)ccn2c1C(=O)O
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14 mg (0.04 mmol) of 8-[(2,6-difluorobenzyl)oxy]-7-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 112A, 20 mg (0.06 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 17 mg (0.17 mmol) of 4-methylmorpholine were initially charged in 0.28 ml of DMF. 7.5 mg (0.06 mmol) of (2R)-2-aminohexan-1-ol were then added, and the mixture was stirred at RT overnight. Another 2.6 mg of TBTU, 4 mg of 4-methylmorpholine and 1 mg of (2R)-2-aminohexan-1-ol were added, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated and purified by thick-layer chromatography (mobile phase: dichloromethane/methanol=10/1). This gave 12 mg (66% of theory; purity 99%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[C:9]1(/[CH:15]=[CH:16]/B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CN(C=O)C>[CH:16](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cc(Br)co1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CN(C)C=O
Product: O=Cc1cc(/C=C/c2ccccc2)co1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and trans-phenylvinyl-boronic acid (1.4 g, 9.4 mmol, 1.5 equiv) using the conditions used to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that the reaction was run in DMF (25 mL). The resulting residue was purified via ISCO Companion (0-30% EtOAc/heptane) and preparative HPLC using the Chromeleon purification system (0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min)) afforded a clean product, retention time of product: 3.4-3.6 min. Amount of (E)-4-styrylfuran-2-carbaldehyde isolated: 89.1 mg (7% yield). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.62 (d, J=0.59 Hz, 1 H), 7.91 (s, 1 H), 7.63 (d, J=0.63 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.35-7.42 (m, 2 H), 7.26-7.32 (m, 1 H), 7.08 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](=[O:22])[CH:20]=[CH2:21].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)s1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7.35 g (27.1 mmol) of 2-(3-chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone (Example 63, Step A) and acrylic acid methyl ester (2.81 mL, 31.2 mmol) in DCM (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.05 mL, 27.1 mmol) in DCM (10 mL) slowly at 0° C. over 20 min. Then the reaction was allowed to warm to ambient temperature. After being stirred at 25° C. for two days, the reaction mixture was diluted with DCM and washed with 2N HCl, water and sat. aq. NaCl solution. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a pre-packed silica gel column (220 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provided the title compound as a light-yellow oil. Mass Spectrum (ESI) m/z=357 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:18].[OH-].[Na+].OO>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1Cc1ccccc1C2=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
200 g of a paste which contains 95 g of 4-aminoanthrone and also contains sulphuric acid, and which is obtained in accordance with the instructions of Example 2, are suspended in 1 l of water and neutralized with concentrated sodium hydroxide solution, and the 4-aminoanthrone is filtered off. It is equally possible to start from the corresponding amount of 4-aminoanthrone which has been obtained according to Example 5 or 6. The 4-aminoanthrone is now stirred into 1 l of water, 150 ml of potassium waterglass (d = 1.25) are added, the mixture is warmed to 60° C and 500 ml of 6% strength hydrogen peroxide solution are added dropwise in the course of 2 hours. This causes the color of the suspension to change from yellow to red. The mixture is stirred for a further 3 hours and is filtered, and the residue is washed until neutral. After drying, 100 g of 1-aminoanthraquinone of 90% purity (89% of theory) are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([O:17][CH3:18])[CH:3]=2)[C:23]([O:26][CH3:27])=[N:24][CH:25]=1
Reactant: COc1ncc(Cl)cc1B(O)O
Reactant: COc1cc(Br)ccc1C(C)N[S@](=O)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)N
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-2-hydroxyacetophenone (0.460 g, 2.0 mmol), titanium tetraethoxide (1.0 g, 4.0 mmol) and (R)-2-methyl-2-propanesulfinamide (0.266 g, 2.2 mmol) in dichloromethane (3.0 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was cooled in ice and added to a stirred mixture of sodium borohydride (0.30 g, 8.0 mmol) in tetrahydrofuran (50 ml). This mixture was stirred for 1 h at ambient temperature, treated with brine (30 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated The residue was flash chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide. A mixture of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide (0.130 g, 0.4 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid (0.150 g, 0.8 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol), 2M aqueous sodium carbonate solution (2 ml), toluene (1 ml) and ethanol (1 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the residue dissolved in methanol. This solution was treated with 2M hydrogen chloride in diethyl ether solution. After standing for 2 hours, the mixture was poured onto an SCX column, washed with methanol and then eluted with 1M ammonia in methanol solution. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine instead of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. MS (ESI) m/z: 505.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[N:21][OH:22])[NH2:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[C:38](C1NC=CN=1)(C1NC=CN=1)=[O:39].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][C:38](=[O:39])[O:22][N:21]=4)[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C(N)=NO)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Yield: 79.7 %

Procedure:
A mixture of Example 8C (2.62 g, 5.0 mmol), carbonyl diimidazole (0.973 g, 6.00 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.829 mL, 5.50 mmol) in dioxane (20 mL) was refluxed for one hour, cooled and partitioned between ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate/hexane (1:3) to give the title compound as a solid (2.19 g, 80%).