Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[ClH:17].[Cl:18]Cl>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]2[O:9][C:8]([Cl:18])([Cl:17])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Cc1cccc2c1OCO2
Reactant: ClCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc2c1OC(Cl)(Cl)O2

Procedure:
160 g of 4-methyl-1,3-benzodioxole are added dropwise to 276 g of phosphorus pentachloride in 840 ml of carbon tetrachloride (prepared from phosphorus trichloride and chlorine), with stirring. Vigorous evolution of hydrogen chloride starts immediately. Towards the end of the reaction, 85 g of chlorine are passed in at about 20° C. and when the evolution of gas has ended, the mixture is then heated under reflux. By distillation, the phosphorus trichloride and carbon tetrachloride are recovered and the 4-methyl-2,2-dichloro-1,3-benzodioxole is then obtained at boiling point: 98-99° C. (22 mbar).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[CH:32]=[CH:31][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([Cl:26])[N:23]3[N:27]=[C:28]([CH3:30])[CH:29]=[C:22]3[N:21]=2)=[O:18])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].P([O-])([O-])([O-])=O>C1COCC1>[Cl:26][C:24]1[N:23]2[N:27]=[C:28]([CH3:30])[CH:29]=[C:22]2[N:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:31]=[CH:32][C:13]([C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[CH:14][CH:15]=2)[CH:25]=1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc3)cc(Cl)n2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Reaction time: 60 h

Procedure:
4-(1-(tert-Butyldimethylsilyloxy)-2-methylpropan-2-yl)-N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (4F, 3.9 g, 1.0 equivalent) was dissolved in THF (0.13 M) and treated with TBAF (1.0 M in THF, 4.0 equivalents). After 60 hours, pH 7 phosphate buffer was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (SiO2, gradient of 25 to 50% EtOAc/hexanes) to give N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6 H), 2.44 (s, 3 H), 3.46 (d, J=5.05 Hz, 2 H), 4.76 (t, J=5.31 Hz, 1 H), 6.45 (s, 1 H), 7.52 (d, J=8.59 Hz, 2 H), 7.99 (d, J=8.59 Hz, 2 H), 8.06 (s, 1 H), 11.30 (s, 1 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([Cl:8])=[O:7].[C:9]1([CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]2[CH3:25])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[ClH:8].[C:9]1([CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][C@@H:22]([CH3:24])[N:21]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:20][C@@H:19]2[CH3:25])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1CN(CCCc2ccccc2)[C@@H](C)CN1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: C[C@@H]1CN(CCCc2ccccc2)[C@@H](C)CN1C(=O)c1ccco1
Product: Cl

Procedure:
2-Furoyl chloride (13 g) was added dropwise to a solution of trans-1-(3-phenylpropyl)-2,5-dimethylpiperazine [b.p. 138 - 140 (4 mmHg), dipicrate, m.p. 258° - 261°C] (21 g) and benzene (200 ml).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>O1CCOCC1>[CH3:12][C:8]1([CH3:13])[CH2:7][C:6]2=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9]1
Reactant: CSc1sc(Br)c2c1C(=O)CC(C)(C)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1COCCO1
Product: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Yield: 56 %

Procedure:
1-Bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (300 mg, 1 mmol) was dissolved in dioxane (25 mL), and 2-(tri-n-butylstannyl)pyridine (550 mg, 1.35 mmol) was added. The solution was de gassed with nitrogen then tetrakis (tri-phenylphosphine)palladium (30 mg, 0.025 mmol) was added and the solution refluxed for 16 h. The solvent was then removed in vacuo and the residue triturated with a mixture of ethyl acetate and hexane (1:3). After filtration the solid product was washed with a little diethyl ether to give the title compound as a white solid (170 mg, 57%). mp 217-220° C. Found: C, 63.02; H, 5.64; , 4.47%. C16H17NOS2 requires: C, 63.36; H, 5.61; N, 4.62%. 1H NMR (250 MHz, CDCl3)δ1.08 (6H, s), 2.44 (2H, s), 2.65 (3H, s), 2.93 (2H, s), 7.18 (1H, m), 7.47 (1H, d, J=8Hz), 7.71-7.77 (1H, m), 8.61-8.63 (1H, m). MS (ES+) 304 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(O)C.S(=O)(=O)(O)O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]2[CH2:23][C:24]3[C:3]4[C:4](=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[NH:9][C:25]=3[CH2:26][CH2:27]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NNc1cc(F)cc(F)c1
Reactant: O=C1CCC(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=S(=O)(NC1CCc2[nH]c3cc(F)cc(F)c3c2C1)c1ccc(Cl)cc1

Procedure:
14.0 g (97 mmol) of the compound of Example I and 27.95 g (97 mmol) of 4-chloro-N-(4-oxo-cyclohexyl)-benzenesulphonamide are refluxed for 5 hours in 190 ml of ethanol and 36 ml of concentrated sulphuric acid, then the mixture is cooled and diluted with 300 ml of water. The mixture is extracted 4 times using 250 ml of ethyl acetate each time, and the organic phase is dried using sodium sulphate, filtered with suction over kieselguhr and evaporated. The residue is stirred with methylene chloride and dried in a high vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][N:32]1[C:38]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=2[CH:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:35]([NH2:50])[CH2:34][C:33]1=[O:51]>C(OCC)(=O)C>[CH3:31][N:32]1[C:38]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=2[CH:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:35]([NH:50][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:34][C:33]1=[O:51]
Reactant: CN1C(=O)CN(N)C(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CN1C(=O)CN(NC(=O)CNC(=O)OCc2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4.2 g. (0.02 moles) of benzyloxycarbonyl-glycine and 4.0 g. (0.02 moles) of dicyclohexyl carbodiimide are added to a solution of 6.0 g. (0.02 moles) of 1-methyl-4-amino-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 200 ml. of ethyl acetate. The reaction mixture is stirred at room temperature overnight, thereafter the separated dicyclohexyl urea is filtered off, and the filtrate is evaporated under reduced pressure. The residue is admixed with acetonitrile, the solution is boiled, the separated dicyclohexyl urea is filtered off from the hot solution, and the filtrate is allowed to cool. The separated crude product is filtered off, and crystallized from ethanol. 7.1 g. (72%) of 1-methyl-4-(N-benzyloxycarbonyl-glycylamino)-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 184°-190° C.; Rf(1) = 0.3.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[C:14]([CH2:15][OH:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)([O-:8])=[O:7].CCN(CC)CC.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([O:16][CH2:15][C:14]1[CH:13]=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7])=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(COC(=O)CBr)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.1 %

Procedure:
Bromoacetylbromide (0.19 ml, 2.2 mmol) was slowly added to the solution of 6-nitroveratrylalcohol (0.43 g, 2 mmol), Et3N (0.56 ml, 4 mmol) and DMAP (24 mg, 0.2 mmol) in CHCl3 (5 ml). After stirring at room temperature for five hours, CH2Cl2 (20 ml) was added and the mixture was washed with HCl (1 M, 2×10 ml), NaHCO3 (sat., 10 ml) and water (10 ml). Organic phase was dried over Na2SO4, evaporated and purified by chromatography (Si-gel, CH2Cl2) to yield 4.5-dimethoxy-2-nitrobenzyl 2-bromoacetate (368 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH2:13][S:14][CH2:15][CH3:16])[C:6](=[O:17])[C:5]2([CH3:19])[CH3:18].CS[C:22](SC)=[N:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:15]([S:14][CH2:13][CH2:12][N:7]1[C:8]2[CH:9]=[C:10]3[NH:11][C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:18])([CH3:19])[C:6]1=[O:17])[CH3:16]
Reactant: CSC(=NC(=O)c1ccccc1)SC
Reactant: CCSCCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Solvent: CN(C)C=O
Product: CCSCCN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Yield: 71.2 %

Procedure:
A solution of B30 (0.73 g) and N-(bis-methylsulfanyl-methylene)-benzamide (0.72 g; 2.70 mmol) in dry N,N-dimethylformamide (35 ml) is stirred at 80° C. for 18 h. The mixture is evaporated to dryness and the residue is purified by preparative RP-MPLC eluted with MeCN/water to yield the desired compound (0.76 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:7]=1.[CH3:13][NH2:14]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:14][CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: CN
Reactant: ClCCCOc1cncc(Br)c1
Solvent: CO
Product: CNCCCOc1cncc(Br)c1
Temperature: 102 °C

Procedure:
Crude 3-bromo-5-(3-chloropropoxy)pyridine (4.07 g) from the previous step was dissolved in CH3OH (28 mL) and added to a 40 wt % solution of methylamine (35 mL) in a heavy-walled pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 102° C. for 4 h. After cooling, the solution was concentrated by rotary evaporation, a saturated NaCl solution (15 mL) was added, and the mixture was basified with 10% NaOH solution (5 mL). The mixture was extracted with CHCL3 (4×30 mL). The combined CHCL3 extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 2.07 g of a brown oil. The product was purified by column chromatography on silica gel (100 g) eluting with CHCL3 --CH3OH (9:1, v/v) to remove impurities, followed by CHCL3 --CH3OH--Et3N (75:25:2, v/v/v) to collect the product. Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCL3 (25 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 0.79 g (29.5% based upon 5-bromo-3-hydroxypyridine) of an amber-brown oil, which tended to crystallize as light amber crystals. 1H NMR (CDCl3, 300 MHz): δ 8.27 (d, 1H, J=1.85 Hz), 8.24 (d, 1 H, J=2.48 Hz), 7.38 (dd, 1H, J=1.91, 1.91 Hz), 4.09 (t, 2H, J=6.22 Hz), 2.78 (t, 2H, J=6.84 Hz), 2.47 (s, 3H), 1.99 (p, 2H, J=6.56 Hz), 1.53 (br s, 1H).
Reaction SMILES: [F:1][C:2]([C:7]1[N:12]=[CH:11][C:10]2[C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:9]=2[CH:8]=1)([F:6])[CH2:3][CH2:4][CH3:5].Cl[CH2:19][C:20](Cl)=[O:21].[C:23]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[NH:33][CH2:32][C@H:31]1[CH3:43])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.N1C=CC=CC=1>[C:23]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([CH2:36][N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[N:33]([CH2:19][C:20]([N:15]2[C:9]3[CH:8]=[C:7]([C:2]([F:6])([F:1])[CH2:3][CH2:4][CH3:5])[N:12]=[CH:11][C:10]=3[C:13]([CH3:16])([CH3:17])[CH2:14]2)=[O:21])[CH2:32][C@H:31]1[CH3:43])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1CN[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A stirred solution of 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (100 mg, 0.42 mmol) in DCM (5 mL) and pyridine (0.5 mL) at 0° C. was treated with chloroacetyl chloride (0.036 mL, 0.46 mmol). After 2 h the solution was treated with (2R,5S)-2-methyl-5-morpholin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.42 mmol) and further pyridine (0.5 mL). After overnight stirring at room temperature no coupling had occurred: the mixture was concentrated in vacuo, diluted with DMF (3 mL), treated with DMAP (1 mg) and heated to 75° C. After 6 h, LC/MS showed ˜80% progression. The mixture was cooled and partitioned between DCM and water. The aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated to dryness. Purification by preparative HPLC gave a pale brown glass (30 mg, 12%). MS: [M+H]+=580
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:9]2)[CH:3]=1>C(OC(=O)C)(=O)C>[C:23]([O:25][CH2:26][C:7]1[N:2]=[CH:3][C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:9]2)=[CH:5][CH:6]=1)(=[O:24])[CH3:10]
Reactant: CCOC(=O)c1nn(-c2ccc[n+]([O-])c2)c2c1CS(=O)(=O)c1ccccc1-2
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1nn(-c2ccc(COC(C)=O)nc2)c2c1CS(=O)(=O)c1ccccc1-2
Yield: 191.9 %

Procedure:
A solution of ethyl 1-(1-oxidopyridin-3-yl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (637 mg) in acetic anhydride (30 mL) is heated to 130° C. for 2 h under nitrogen. After completion of the reaction, the reaction mass is concentrated under reduced pressure and triturated in water, filtered and dried to afford 700 mg (99%) of the title compound. MS (ESI+): 442.0.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O.[Cl-].[Na+].O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(NS(=O)(=O)c2ccc(CBr)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2ccc(S(=O)(=O)Nc3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
Add 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2.77 g, 14.2 mmol) to sodium hydride (396 mg, 15.7 mmol) in dimethylformamide (20 mL) at 0° C., stir 10 minutes, add 4-bromomethyl-N-(3-cyano-phenyl)-benzenesulfonamide (2.50 g, 7.12 mmol) in dimethylformamide (15 mL) drop wise via addition funnel. After 2 hours at ambient temperature, pour into brine (40 mL), extract with ethyl acetate (2×40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify residue by flash chromatography to yield the title compound (1.17 g, 2.52 mmol): MS (m/z): 463 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=1.[F:24][C:25]([F:30])([F:29])[CH:26]1[O:28][CH2:27]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:12]=1)[CH2:27][CH:26]([OH:28])[C:25]([F:30])([F:29])[F:24]
Reactant: Fc1ccc(F)c(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Temperature: 50 °C
Yield: 83.5 %

Procedure:
EX -661 B) The N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amine (2.22 g, 6.67 mmol) product from EX-661A and 1,1,1-trifluoro-2,3-epoxypropane (1.12 g, 10 mmol) were dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0.33 mmol) was added, and the stirred solution was warmed to 50° C. for 2 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 2.49 g (84%) of the desired 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C18H14F9NO2: 448.0959 [M+H]+, found: 448.0940.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.[I-].[Na+]>CO>[CH:23]1([CH2:26][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCC3CC3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) were added cyclopropylmethyl bromide (2.3 μL, 0.019 mmol) and sodium iodide (1 mg, 7 μmol) at room temperature, which was stirred for 2 hours at 60° C. The reaction mixture was cooled to room temperature and then purified as is by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). The eluate was neutralized by triethylamine while being concentrated. The solvent was evaporated under a reduced pressure. The residue was washed with water to obtain the title compound (1.6 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=4[CH3:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:23][OH:24])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of [9-chloro-1-(4-bromo-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (4.68 g, 11.5 mmol) in dimethylsulfoxide (80 mL) was added Dess-Martin reagent (5.37 g, 12.7 mmol), and the mixture was stirred at room temperature for 1 h. To the reaction mixture was added Dess-Martin reagent (0.49 g, 1.15 mmol), and the mixture was stirred at room temperature for 1 h. To the reaction mixture was added Dess-Martin reagent (1.46 g, 3.45 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture diluted with ethyl acetate, and the mixture was quenched by saturated aqueous sodium hydrogen carbonate. The solid was removed by filtration. The filtrate was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow powder (4.54 g, 11.2 mmol, 97%).
Reaction SMILES: C([O:4][C:5]1[CH:16]=[CH:15][C:8]2[CH:9]=[C:10]([C:12](=[O:14])[CH3:13])[O:11][C:7]=2[CH:6]=1)(=O)C.C(NC(C)C)(C)C.[Li].[C:25](Cl)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:4][C:5]1[CH:16]=[CH:15][C:8]2[CH:9]=[C:10]([C:12](=[O:14])[CH2:13][C:25](=[O:34])/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:11][C:7]=2[CH:6]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(=O)Oc1ccc2cc(C(C)=O)oc2c1
Agent: Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)CC(=O)c1cc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
To a solution of the crude 2-acetyl-1-benzofuran-6-yl acetate (0.23 g) in tetrahydrofuran (5 mL) at −78° C. was added lithium diisopropylamine (2.0 N solution in THF, 1.63 mL, 3.25 mmol). The mixture was stirred at the same temperature for 20 min prior to the addition of cinnamoyl chloride (0.22 g, 1.3 mmol). The reaction was warmed slowly to room temperature and stirred overnight. The reaction was treated with 1.0 N aqueous hydrochloric acid solution (10 mL) at 0° C. and diluted with ethyl acetate (250 mL). The organic layer was washed with 2N aqueous hydrochloric acid (100 mL), saturated aqueous sodium chloride (60 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude product. Purification on silica (gradient 8:2 to 6:4, hexanes/ethyl acetate) afforded the product (0.12 g, 30% yield) as a yellow solid: MS (EI) for C19H14O4: 307 (MH+).
Reaction SMILES: C1COCC1.[CH3:6][C:7]([CH3:20])([CH3:19])[CH2:8][O:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H][H]>CO>[CH3:6][C:7]([CH3:20])([CH3:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1
Reactant: CC(C)(C)COCc1ccc(C#N)cc1
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)COCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Add 1M BH3-THF complex in THF (16 mL, 16 mmol) to neat 4-(2,2-dimethyl-propoxymethyl)-benzonitrile (3.043 g, 15 mmol) and stir the mixture overnight at room temperature. Add methanol and stir until hydrogen evolution stops. Concentrate the solution in vacuo. Dissolve the crude mixture in methanol and filter through an SCX column eluting with methanol followed by 3M ammonia in methanol. Concentrate in vacuo to obtain the title compound (3g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22](O)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 75A in analogy to the synthesis of the compound of Example 1. 23 mg (39% of theory) of the title compound are obtained.