Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.[OH:8][C:9]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:10]=1C=O.C(=O)([O-])O.[Na+].C(N(C(C)C)CC)(C)C.[CH3:35][O:36][CH2:37]Cl>CO.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>[CH3:7][O:6][CH:1]([O:4][CH3:5])[C:10]1[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([F:18])([F:19])[F:20])[C:9]=1[O:8][CH2:35][O:36][CH3:37]
Reactant: O=Cc1cccc(C(F)(F)F)c1O
Reactant: COCCl
Reactant: COC(OC)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: COCOc1c(C(OC)OC)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
After trimethyl orthoformate (130 ml, 1.19 mol) and camphorsulfonic acid (1.55 g, 6.67 mmol) were added to a solution of 2-hydroxy-3-(trifluoromethyl)benzaldehyde (31.7 g, 167 mmol) obtained in Example (6-3) in methanol (50 ml), the mixture was stirred at 50° C. for 6 hours. After the reaction mixture was poured into a 1% aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by concentrating the organic layer was dissolved in methylene chloride (400 ml) and diisopropylethylamine (50.9 ml, 292 mmol) and chloromethyl methyl ether (15.4 ml, 203 mmol) were successively added thereto under ice-cooling, and the mixture was stirred overnight. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (twice), the organic layer was successively washed with 0.5N hydrochloric acid, a 5% aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=14/1-10/1) to give 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene as a pale yellow oil (42.2 g, yield: 93%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH2:65])=[N:62][CH:61]=1)=[O:59])[CH3:56]>C(Cl)Cl>[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH:65][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:62][CH:61]=1)=[O:59])[CH3:56]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 98 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (717 mg, 1.62 mmol), triethylamine (420 μL, 3.03 mmol), and 2-amino-thiazole-5-carboxylic acid ethyl ester: (279 mg, 1.62 mmol) in methylene chloride (10 mL) was stirred at 25° C. under nitrogen for 14 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 10/11 hexanes/ethyl ether) afforded 2-[3-cyclopentyl-2(-4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (448 mg, 98%) as a white solid: mp 100-103° C.; EI-HRMS m/e calcd for C21H26N2O5S2(M+) 450.1283, found 450.1285.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:50])[CH:30]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]([S:35]CC3C=CC(OC)=CC=3)[NH:32]2)=[CH:27][C:26]=1[F:51]>>[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:50])[C:30]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:31]([SH:35])[NH:32]2)=[CH:27][C:26]=1[F:51]
Reactant: CCOC(=O)C1C(=O)c2cc(F)c(Cl)cc2NC1SCc1ccc(OC)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1c(S)[nH]c2cc(Cl)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
To 1.7 ml (0.01896mol) of trifluoromethane sulfonic acid were added 2.06 mol (0.0189 mol) of anisole and 8.8 ml (0.11378 mol) of trifluoroacetic acid and the mixture was cooled at 0° C. in an ice-sodium chloride bath. With stirring, 2.0 grams (0.0047 mol) of ethyl 7-chloro-6-fluoro-2-(4-methoxybenzylthio)-4-oxo-dihydroquinoline-3-carboxylate was added thereto and the mixture was stirred for about twenty minutes. Then trifluoroacetic acid and anisole were evaporated therefrom under reduced pressure and 15 grams of ice water was added to the residue. Yellow crystals appeared immediately. The crystals were collected by filtration, washed with water, dried, and recrystallized from dimethyl formamide and ether to give ethyl 7-chloro-6-fluoro-2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylate. Yellow crystals. Yield 1.4 grams (98 percent). Melting point 221° to 223° C. (decomposition). Elementary analysis calculated as C12H19ClFNO3S: C 47.-7, H 3.01, N 4.64; Found: C 47.81, H 3.25, N 4.81.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[N:5]=[CH:4][N:3]=1.[CH2:19]([N:21]([CH2:24]C)[CH2:22]C)C.ClC(OC1C=CC=CC=1)=[O:28].CNC>O1CCCC1.C(OCC)C.CO>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:19](=[O:28])[N:21]([CH3:24])[CH3:22])[CH:7]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (500 mg) was dissolved in tetrahydrofuran (10 ml) under a nitrogen atmosphere, and then triethylamine (0.418 ml) and phenyl chloroformate (0.376 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 1 hr and 10 min. Triethylamine (0.139 ml) and phenyl chloroformate (0.125 ml) were added further thereto while cooling in an ice bath, followed by stirring at room temperature for 30 min. Triethylamine (0.139 ml) and phenyl chloroformate (0.125 ml) were added further thereto, followed by stirring at room temperature for 30 min. To the reaction mixture was added 2 M dimethylamine (a methanol solution) (5.0 ml), followed by stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then suspended in diethyl ether. The solid was filtered, and dried under aeration to provide the titled compound (378.9 mg, 59.0%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=O>C(O)CCC>[F:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])=[N:9][CH2:10][C:11]3[N:12]([C:24]([CH2:23][O:22][CH3:21])=[N:26][N:27]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1C(c1ccccc1Br)=NCC(=S)N2
Reactant: COCC(=O)NN
Solvent: CCCCO
Product: COCc1nnc2n1-c1cccc(F)c1C(c1ccccc1Br)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6-fluoro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 7-fluoro-1-(methoxymethyl)-6-(o-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(C2COC(=O)C2)CCCC1.O[Li].O>C(O)(C)C.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[C:3]([OH:18])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)C1CCCC1
Agent: O=C1CC(C2CCCC2)CO1
Agent: [Li]O
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)CC(C(=O)O)C1CCCC1
Yield: 67.9 %

Procedure:
Preparation of 4-Cyclopentyl-dihydro-furan-2-one 2-Cyclopentyl-succinic acid 4-tert-butyl ester 1-methyl ester (13.4 g, 52.3 mmol) and LiOH.H2O (2.8 g, 66.7 mmol) are stirred in 200 mL of 3:1 isopropanol/H2O at room temperature overnight. The isopropanol is evaporated, and the aqueous solution is extracted with Et2O (3×100 mL). The aqueous phase is acidified to pH=4 with saturated KH2PO4 and extracted with Et2O (3×100 mL). The Et2O is dried over MgSO4 and evaporated to give 8.6 g (68% yield) of 2-cyclopentyl-succinic acid 4-tert-butyl ester. NMR (1H, 400 MHz, CDCl3) δ1.1-1.3 (2H, m); 1.4 (9H, s); 1.5 (4H, m); 1.7 (2H, m); 1.9 (1H, m); 2.4 (1H, dt); 2.6 (2H, m). The product is carried on.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OCC4C=CC=CC=4)=O)[CH2:16][CH2:15]3)[CH:9]=2)[N:5]=[C:4]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=3)[N:31]=2)[N:3]=1.C[C:47]([OH:49])=[O:48]>Br>[F:45][C:42]([F:43])([F:44])[C:47]([O-:49])=[O:48].[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][NH2+:17][CH2:16][CH2:15]3)[CH:9]=2)[N:5]=[C:4]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([F:45])([F:43])[F:44])=[CH:39][CH:40]=3)[N:31]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: CC(=O)O
Agent: Br
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CC[NH2+]CC2)c1
Product: O=C([O-])C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of benzyl 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate (200 mg, 0.30 mmol) in AcOH (1 mL), HBr (2 mL, 48% in H2O) was added at RT. The mixture was stirred at 40° C. for 1 h, and then concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (Mobile phase: A=0.01% TFA/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-ium 2,2,2-trifluoroacetate as a white solid (130 mg, 84%). MS (ES+) C22H21F3N8O2 requires: 486. found: 487 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 2H), 8.22 (d, J=8.5 Hz, 2H), 8.15 (d, J=5.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 6.57 (d, J=5.0 Hz, 1H), 5.54 (s, 2H), 3.73-3.71 (m, 4H), 3.22-3.19 (m, 4H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:17]=[C:16]([O:18]C(=O)CC)[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[C:8]=1C(=O)CC)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.CCOCC.C(Cl)Cl>O>[CH2:1]([C:3]1[O:4][C:5]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[CH:8]=1)[CH3:2]
Reactant: CCC(=O)Oc1ccc2c(=O)c(C(=O)CC)c(CC)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCc1cc(=O)c2ccc(O)cc2o1
Reaction time: 9 h
Yield: 59.9 %

Procedure:
A suspension of 6.5 g (21.5.10-3 mol) of 2-ethyl-7-(1-oxopropoxy)-3-(1-oxopropyl)-4H-1benzopyran-4-one and 5 g (47.403 mol) of sodium carbonate in 65 ml of water is kept at a temperature of 150° C. for 9 hours. The reaction mixture is hydrolyzed with a 1N solution of hydrochloric acid. The product is extracted with ethyl acetate. After purification by chromatography on silica gel using an ether/methylene chloride mixture (1/2 v/v) as the eluent, 2.45 g (yield: 61%) of the expected product are obtained.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O-])(O)=O.[Na+].[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)=[NH:24])([CH3:12])[CH3:11].C(N)(C)C>O.C(OCC)(=O)C>[CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:10]([CH3:11])[CH3:12])[C:14]=1[N:22]1[CH:3]=[CH:2][N:24]=[C:23]1[C:25]1[CH:26]=[C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)([CH3:21])[CH3:20]
Reactant: O=CCCl
Reactant: COc1cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)cc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)N
Product: COc1cc(-c2ccccc2)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Yield: 98.4 %

Procedure:
To a 250 mL round bottom flask was mixed 2-chloroacetaldehyde (5.36 g, 34.2 mmol), NaHCO3 (2.87 g, 34.2 mmol), N-(2,6-diisopropylphenyl)-5-methoxy-[1,1′-biphenyl]-3-carboximidamide (6.6 g, 17.08 mmol) were charged in a flask and 100 mL of iso-propyl amine was added. The reaction mixture was heated up to reflux for 3 hours. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. After silica gel chromatography with 10% ethyl acetate in hexane as solvent, 6.9 g of product was obtained.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(O)C>[O:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:36][CH:37]=2)[CH2:21][CH2:22]1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCCCCCCOc1ccc(CN2CCOCC2)cc1
Solvent: CCO
Product: O=c1c(NCCCCCCOc2ccc(CN3CCOCC3)cc2)c(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione (350 mg, 1.6 mmol) in ethanol (1.4 mL) was added 6-[4-(morpholinomethyl)-phenoxy]-hexylamine (469 mg, 1.6 mmol) in ethanol (5 mL). The reaction was allowed to stir at r.t. for 18 h, then filtered. The solid was washed with cold ethanol, then ether to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:20])=[C:17](Br)[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:20])=[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(N)c(Br)c2)c(SC)s1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(N)c(-c3ccccc3C)c2)c(SC)s1
Temperature: 80 °C
Yield: 29 %

Procedure:
The procedure as in Example 1: step c was followed using 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.06 mmol, Example 124: step a), 2-methyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M, 400 μL, 0.5 mmol), ethanol (400 μL) and toluene (800 μL). The reaction was heated to 80° C. for 12 hours. The residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by preparative SiO2 TLC purification (20% MeOH in DCM) that yielded the title compound (7.4 mg, 29%) as a white solid. ESI-MS (m/z): Calcd. for C19H18N2O4S3: 420.0 (M+1) found: 420.2.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BrH:11]>C1(C)C=CC=CC=1>[Br:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCCCCO
Reactant: Br
Solvent: Cc1ccccc1
Product: OCCCCCCCCBr

Procedure:
In a 6 m3 kettle, 235 kg of octane-1,8-diol were stirred under reflux with 3 m3 of toluene and 440 kg of HBr (48% strength) for 40 hours. The aqueous phase was then separated off. The toluene phase was thoroughly washed with 500 1 of water, then with 500 l of 10% strength sodium carbonate solution and then again with 500 1 of water. A sample was concentrated and was found to contain 92% of bromooctanol in addition to 1.9% of dibromooctane and 2.0% unconverted octanediol. After removal of the toluene by distillation in the reaction kettle and a Sambay distillation of the remaining residue, the yield was 254 kg (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH:6]=[O:7].[C:20]([Mg]Cl)#[CH:21]>C1COCC1>[OH:7][CH:6]([C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]#[CH:21]
Reactant: COc1cc(C=O)ccc1OCCN1CCOCC1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCCN2CCOCC2)c(OC)c1

Procedure:
3-Hydroxy-3-[3-methoxy-4-[2-(4-morpholinyl)-ethoxy]-phenyl]-1-propyne was prepared according to Method A above from 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde (0.60 g, 2.26 mmol) (see below) in THF (25 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 502 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH:12]=[CH:13][O:14]CC)[CH:6]=2.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=[O:14])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC=Cc1cnc2cc(Br)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=CCc1cnc2cc(Br)cnc2c1
Yield: 95 %

Procedure:
To a mixture of the product from Example 153C (0.25 g, 0.89 mmol) in 15 mL of THF was added 1.5 mL of HCl (6N). The mixture was heated to reflux for 5 hr, cooled and the pH adjusted to 8.0 with NaOH. The mixture was diluted with 75 mL of CH2Cl2 and washed successively with a saturated solution of sodium bicarbonate, brine and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the desired product in 95% yield. 1H NMR (CDCl3, 300 MHz) δ3.75 (m, 2H), 8.25 (m, 1H), 8.60 (m, 1H), 8.85 (m, 1H), 9.00 (m, 1H), 9.90 (s, 1H). MS (ESI) [M+H]+ at 252.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([NH2:32])[N:23]=1.Cl.C(O)C>O>[NH2:32][C:24]1[N:23]=[C:22]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
19.0 mg (0.071 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water. 0.1 ml (0.1 mmol) of 1N hydrochloric acid is added, and the mixture is heated at reflux overnight. 3 ml of ethanol and a further 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added. The mixture is stirred at 100° C. for another 6 hours. The mixture is concentrated slightly and the pH is adjusted to 10 using 1N aqueous sodium hydroxide solution, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 10:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].II.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17]2=[O:25]>CCOCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17]2([OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1=O
Reactant: COc1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(=O)Nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
5.57 g of 1-bromo-2-methoxybenzene are added dropwise to a suspension of 0.72 g of magnesium in 15 ml of ether containing a few crystals of iodine, the reflux being maintained once it has started. At the end of the addition, the mixture is refluxed for 2 hours. A suspension of 2.7 g of 5,6-dichloro-1H-indole-2,3-dione in 30 ml of THF is then added and the mixture is refluxed for 30 minutes. After cooling to RT, the reaction mixture is poured into a water/ice/concentrated HCl mixture and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is slurried in hot iso ether and the precipitate formed is spin-filtered off and washed with ether. 3 g of the expected product are obtained.