Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:7]=1.CCOCC.Cl.C(Cl)(Cl)Cl.CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[N:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-n1nc(C(F)(F)F)cc1C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1nc(C(F)(F)F)cc1CN
Temperature: 0 °C
Yield: 74 %

Procedure:
To a stirred solution of 1-(5-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (3.09 g, 10.27 mmol, 1.0 eq) in THF (40 mL) was added BH3-DMS (2.30 g, 30.81 mmol, 3.0 eq) at 0° C. and heated to reflux for 1 h. The reaction mixture was cooled to 0° C. and quenched with 1N HCl and basified with 1N solution of NaOH to a pH of ˜10 and the mixture extracted with ethyl acetate (100 mL×2), dried (Na2SO4), the solvent evaporated to get a pale yellow oil. The oil was treated with ether and HCl to get (1-(5-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (1.3 g, 20% yield over 3 steps) as white solid (TLC system: CHCl3/MeOH (9:1), Rf 0.5).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)O1.Br[C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[CH:32][CH:31]=2)[N:26]=1.C([O-])(O)=O.[Na+].O1CCOCC1>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.O>[F:43][C:37]([F:42])([O:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH:28]=[N:29][C:25]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=3)=[N:26]2)=[CH:31][CH:32]=1)[C:38]([F:41])([F:40])[F:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A microwave vial was charged with tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (178 mg, 0.559 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, and the capped reaction mixture was heated at 140° C. for 30 min in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. Water (3 mL) was added to the solution, and a gummy solid formed, which was filtered and air-dried. Recrystallization of this material from MeOH/water gave the title compound as a white solid (180 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H), 6.61 (s, 1H), 1.54 (s, 9H); 19F NMR (376 MHz, CDCl3) 5-85.90, −87.86; ESIMS m/z 470 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:5])=[O:4].[C:15](Cl)(Cl)=[O:16]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[C:10]([N:12]=[C:15]=[O:16])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:5])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1cc(N)ccc1Cl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1cc(N=C=O)ccc1Cl

Procedure:
50 g of N,N-dimethyl-2-chloro-5-aminobenzenesulfonamide (Example A-3 above) was treated with an excess of phosgene in ethyl acetate as is generally described in "Organic Functional Group Preparations" by S. R. Sandler and W. Karo on pages 364-365 (Academic Press, N.Y., 1983) (preparation of organic isocyanates), which disclosure is herein incorporated by reference. 48 g of the title compound was isolated as a tan solid with a melting point of 82°-85° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([NH:5][C:6](OCC)=[O:7])=[S:4].[OH-].[Na+].Cl[O-].[Na+].[OH-].[NH4+:18]>O>[OH:7][C:6]1[N:5]=[C:3]([N:2]([CH3:11])[CH3:1])[S:4][N:18]=1
Reactant: CCOC(=O)NC(=S)N(C)C
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: CN(C)c1nc(O)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 43 g of N,N-dimethyl-N'-ethoxycarbonyl-thiourea, 25 ml of sodium hydroxide and 250 ml of water and a solution of 1M sodium hypochlorite were simultaneously added at 0° to 5° C to 450 ml of concentrated ammonium hydroxide and the reaction mixture was stirred for 2 hours at 0° to 5° C and 3 hours at room temperature. The mixture was evaporated until it congealed into a mass and the mass was adjusted to a pH of 4 with concentrated hydrochloric acid. The mixture was extracted with chloroform and the extracts were dried over magnesium sulfate and were evaporated to dryness. The crystalline residue was washed with petroleum ether (B.p. = 40°-75° C) to obtain 11 g of 3-hydroxy-5-dimethylamino-1,2,4-thiadiazole melting at 142° C and having a Rf = 0.2 (acetone -CHCl3 - 1-1).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C:15]1[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]=[CH:18][CH:19]=1)(=[O:5])=[O:4])[CH3:2]>C(O)C.Cl.[Pt]=O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:8]=1
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(N)cc1C1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To platinum oxide (1.0 g) was added 100C in ethanol (70 mL) and hydrogen chloride (0.6 ml) under nitrogen. The reaction was placed under hydrogen (40 psi). After 3 h the reaction was half done, the catalyst was filtered and the solvent was removed. Fresh platinum oxide was added (1.0 g) and the reaction was stirred under hydrogen (40 psi) for 2 h. The catalyst was filtered over celite and washed with ethanol. The filtrate was neutralized with diethylamine. The solvent was evaporated and the crude residue was redissolved in dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed and the crude product was dried under vacuum to give a white solid 100D (2.0 g).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[C:4]([CH3:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=4)[CH2:29][CH2:30]3)[C:3]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[C:4]([CH3:13])[C:5]=2[O:9]1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2c(Br)cc3c(c2C)OC(C)(C)C3)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(N3CCN(c4ccc(C)cc4)CC3)cc3c(c2C)OC(C)(C)C3)cc1
Temperature: 25 °C
Yield: 3.1 %

Procedure:
To a solution of toluene (10 mL) containing 5-bromo-2,2,7-trimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (300 mg, 0.910 mmol) synthesized in Reference Example 157, 1-(4-methylphenyl)piperazine (160 mg, 0.910 mmol), Tris(dibenzylideneacetone)dipalladium (0) (24.9 mg, 0.027 mmol) and Xantphos (47.2 mg, 0.082 mmol), sodium tert-butoxide (131 mg, 1.36 mmol) was added, and the mixture was stirred under heated reflux for 15 hours. After cooled to room temperature, the reaction solution was subjected to Celite filtration. Water was added to the filtration, and extraction was performed using ethyl acetate. The extract was dried using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. After that, the residue was purified by silica gel chromatography (hexane-ethyl acetate 10:1), and it was crystallized from acetonitrile to obtain 12.0 mg of the title compound as a white solid (yield 3%).
Reaction SMILES: F[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH3:16])[C:5]([C:14]#[N:15])=[C:6]2[C:10]=1[O:9][C:8]([N:11]([CH3:13])[CH3:12])=[N:7]2.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>CS(C)=O.ClCCl>[CH3:12][N:11]([CH3:13])[C:8]1[O:9][C:10]2[C:6](=[C:5]([C:14]#[N:15])[C:4]([CH3:16])=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:2]=2[N:34]2[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]2)[N:7]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C)nc2c1C#N
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
7-Fluoro-2-(dimethylamino)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-132) (0.18 g, 0.61 mmol) was suspended in dimethyl sulfoxide (5 ml), then triethylamine (0.17 ml, 1.23 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.16 ml, 1.26 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), then diisopropyl ether was added, and the insoluble matter was collected by filtration to obtain a pale beige solid (78.5 mg, 33%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[S:38][CH:39]=[C:40]([C:42](O)=[O:43])[N:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:42]([C:40]3[N:41]=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[S:38][CH:39]=3)=[O:43])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1csc(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (7.0 mg, 0.018 mmol), 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (5.2 mg, 0.022 mmol), HATU (17 mg, 0.045 mmol), DMF (0.042 mL) and DIPEA (7.0 mg, 0.054 mmol) were mixed together and the mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give pure sub-title compound as light yellow powder (3.7 mg, 34%). LCMS calc. for C30H34F2N5O5S (M+H)+: m/z=614.2. Found: 614.1.
Reaction SMILES: C(C1C=C([N:10]2[C:14]3[C:15](=[O:26])[N:16](C4C=CC(Br)=CC=4)[CH2:17][CH2:18][C:13]=3[C:12](C)=[N:11]2)C=CC=1F)#N.N#N.CCOC(C)=O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O>[NH:10]1[C:14]2[C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=[N:11]1
Reactant: Cc1nn(-c2ccc(F)c(C#N)c2)c2c1CCN(c1ccc(Br)cc1)C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCCc2cn[nH]c21

Procedure:
1-[3-Cyano-4-fluorophenyl)-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one (Example 47, Part B; 0.23 g, 0.54 mmol), 2-thiomethylphenylboronic acid (0.13 g, 0.76 mmol) and Bu4NBr (0.011 g) in C6H6 (20 mL) and 2N Na2CO3 (4 mL) was purged with a stream of N2 gas. Palladium tetrakis(triphenyl) phosphine (0.032 g, 0.028 mmol) was added and the mixture heated at reflux for 18 h. To the cooled reaction mixture, brine and EtOAc was added and the layers separated. The organic layer was dried (MgSO4) and evaporated then the residue was purified by silica gel chromatography (100 g of SiO2, eluted with 1:1 hexane:EtOAc) to give 0.17 g (3.2 mmol) of 1-[3-cyano-4-fluorophenyl]-3-methyl-6-[2′-thiomethyl)-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one; LRMS (M+H)+: 469.0 m/z.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:4]=1)#[N:2].Br[CH2:35][CH2:36][OH:37].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:35][CH2:36][OH:37])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 10 h
Yield: 94.2 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (170 mg, 355 μmol; Example 5A) was initially charged in dry DMF (4 ml), 2-bromoethanol (177 mg, 1.42 mmol; 4 eq.) and triethylamine (72 mg, 709 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 10 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (175 mg, 94% of theory).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH2:11].Cl[CH2:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH3:21]>CO>[CH3:18][C:19](=[C:20]([CH3:22])[CH3:21])[CH2:23][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH2:11]
Reactant: C=C(c1ccccc1O)n1ccnc1
Reactant: CC(C)=C(C)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccccc1OCC(C)=C(C)C)n1ccnc1
Yield: 63 %

Procedure:
9.2 g (0.23 mol) of sodium hydroxide are added to a mixture of 39.1 g (0.21 mol) of 1-[1-(2-hydroxyphenyl)-vinyl]-imidazole and 200 ml of methanol at room temperature, with stirring. When the addition has ended, the mixture is stirred at 50° C. for a further 30 minutes and is then concentrated under reduced pressure by stripping off the solvent. The solid residue which remains is taken up in 200 ml of dimethylformamide. 24.9 g (0.21 mol) of 1-chloro-2,3-dimethyl-but-2-ene are added to the solution formed at a temperature of 25° C., with stirring. The reaction mixture is stirred at 20° C. for a further 12 hours and then worked up by being concentrated by stripping off the diluent. The residue obtained is chromatographed over silica gel. 35.5 g (63% of theory) of 1-[1-(2-(2,3-dimethyl-but-2-en-1-yl-oxy)phenyl)-vinyl]-imidazole in the form of an oil are obtained in this manner.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O>ClCCl>[CH2:1]([O:3][C:4](=[O:5])/[CH:6]=[CH:31]/[C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([C:27]([F:37])([F:36])[F:26])[CH:29]=1)[CH3:2]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
88.9 g of ethoxycarbonylmethylenetriphenylphosphorane are added dropwise, while cooling, to a solution of 34.0 g of 3-trifluoromethylbenzaldehyde in 400 ml of dichloromethane. The reaction mixture is stirred for one hour at room temperature, the solvent is evaporated off in vacuo and the residue is filtered with ether/hexane (4:1) over silica gel. Concentration by evaporation of the eluate yields the title compound in the form of white crystals; m.p. 40°-41° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2]>C(Cl)(=O)C>[F:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:5]2[C:6]=1[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]2
Reactant: O=C(O)Cc1cccc(F)c1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2cccc(F)c2C(=O)O1
Yield: 102.5 %

Procedure:
2-Carboxymethyl-6-fluoro-benzoic acid (130 mg, 0.65 mmol) in acetyl chloride (2 ml) was heated under microwave irradiation at 150° C. for 10 min then concentrated in vacuo to give the title product (120 mg, 100% yield). The compound is hydroscopic and slowly decomposes back to the starting diacid in wet solvents or under moisturised atmosphere. 1H NMR (500 MHz, DMSO-d6): 4.29 (s, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.34 (dd, J=8.5 Hz, J=11 Hz, 1H), 7.76 (dt, J=5.3 Hz, J=8 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[O:9][C:5]=2[CH:4]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)=O>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][N:14]([C:23]([C:22]4[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=4[O:20][CH3:19])=[O:24])[CH2:13]3)[O:9][C:5]=2[CH:4]=1
Reactant: Clc1ccc2nc(NC[C@@H]3CCNC3)oc2c1
Reactant: COc1cccc(OC)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](CNc2nc3ccc(Cl)cc3o2)C1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 146.3 mg (0.45 mmol) (6-chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine, hydrochloride (intermediate 1), 106.7 mg (0.586 mmol) 2,6-dimethoxy-benzoic acid (commercially available) and 206.9 mg (0.64 mmol) TBTU in 4 mL DMF and 0.3 mL DIPEA was shaken at room temperature over night. The mixture was acidified with formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 72 mg (38%) of the title compound. MS (m/e): 416.2 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(C)=O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:3].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](OC)=[O:24])=[CH:18][CH:17]=1.[H-].[Na+]>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:24])[CH2:1][C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=2)=[O:3])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(Br)cc1

Procedure:
A solution of 5.40 g 4-trifluoromethoxyacetophenone and 7.57 g methyl 4-bromophenylacetate in 60 mL anhydrous THF was treated with 1.59 g 60% NaH for 60 hours. After removing the solvent under reduced pressure, the reaction mixture was diluted with 250 mL ether and washed with 250 mL 0.2 M HCl, 2×100 mL 5% NaHCO3 and 100 mL saturated brine, dried over anhydrous Na2SO4, and evaporated to give a crude product. It was purified on silica gel using 0˜25% EtOAc in hexanes to give title compound as red oil. 1H NMR (CDCl3, 500 MHz) δ 7.86˜7.89 (m, 2H), 7.48˜7.51 (m, 2H), 7.27 (d, J=7 Hz, 2H), 7.17˜7.19 (m, 2H), 6.07 (s, 1H), 3.70 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH2:9][OH:10])=[O:5])[CH3:2].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O.C(OCC)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH:9]=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1C[C@H]1C=O

Procedure:
Cool a solution of (+/−)-trans-2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (0.22 g, 1.53 mmol) in 1.5 mL DMSO to 0° C. Add to the frozen solution triethyl-amine (0.85 mL, 0.62 mmol) followed by sulfur trioxide pyridine (0.49 g, 3.05 mmol). Warm reaction mixture to 12° C. over 3.5 hours, dilute with diethyl ether (80 mL), and wash with 5% aqueous citric acid (3×20 mL) followed by saturated aqueous sodium chloride (1×20 mL). Dry over magnesium sulfate and concentrate under reduced pressure to provide the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:35])[C:17]=1[C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[C:23]=2[CH:22]=[CH:21]1)=[O:19])[C:5]([NH:7][C@H:8]([C:10]([O:12]CC)=[O:11])[CH3:9])=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:35])[C:17]=1[C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[C:23]=2[CH:22]=[CH:21]1)=[O:19])[C:5]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:6]
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of ethyl N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alaninate (20 mg, 0.038 mmol) in tetrahydrofuran and water (1:1, 1 mL) was treated with sodium hydroxide (1.5 mg) and stirred at room temperature for about 1 hour. Tetrahydrofuran was removed under vaccuo and the residue was acidified with hydrochloric acid solution (1N, upto pH 2). The solid was filtered and dried to get pure N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alanine (12 mg, 66%).