Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]([C:20]([N:22]1[CH:26]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:42]([NH:44][C@H:45]([C:51]([NH:53][C@H:54]([CH2:59][OH:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH2:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:25][C@H:24]([OH:61])[CH2:23]1)=[O:21])([CH3:19])[CH3:18])=[O:15].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]([C:20]([N:22]1[CH:26]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:42]([NH:44][C@H:45]([C:51]([NH:53][C@H:54]([CH2:59][OH:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH2:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:25][C@H:24]([OH:61])[CH2:23]1)=[O:21])([CH3:19])[CH3:18])=[O:15]
Reactant: CCCCCCCCCCCCCC(=O)NC(C)(C)C(=O)N1C[C@@H](O)CC1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)CC(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCC(=O)NC(C)(C)C(=O)N1C[C@@H](O)CC1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 13.3 mg of Halovir A in 0.5 mL of pyridine was added 0.5 mL of acetic anhydride and 1.2 mg of N,N-dimethylaminopyridine. The reaction mixture was stirred under nitrogen at ambient temperature for 16 hours. The solvent was removed in vacuo, and the crude mixture was partitioned between 3 mL of saturated sodium bicarbonate and 3 mL of ethyl acetate. The layers were separated and the aqueous layer was washed with 2×3 mL of ethyl acetate. The organic layers were combined and washed with 5 mL each of 1 N HCl and brine, dried over Na2CO3, filtered, and concentrated in vacuo. The crude product was purified by C18 HPLC using 2.5% H2O in methanol. Pure Halovir D was obtained as a colorless oil and was characterized by mass spectrometry, and proton and carbon NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:34]1([C:40](=[S:42])[NH2:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:41][C:9]=2[C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (4.0 g, 10.88 mmol), NBS (2.033 g, 11.42 mmol) and 4-morpholinecarbothioamide (1.749 g, 11.97 mmol) the title compound of Step F was obtained as a yellow solid (5.11 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (br. s., 1H), 8.41-8.51 (m, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.27 (t, J=8.7 Hz, 1H), 6.76 (d, J=5.3 Hz, 1H), 5.88-6.03 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.1 Hz, 1H), 4.61 (d, J=5.1 Hz, 2H), 3.70-3.76 (m, 4H), 3.57 (d, J=4.4 Hz, 4H). MS (ESI): 493 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH2:21][CH:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24])=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)[CH3:4].[C:35]([O:39][C:40](=[O:43])[CH2:41]Br)([CH3:38])([CH3:37])[CH3:36].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:35]([O:39][C:40](=[O:43])[CH2:41][O:24][CH2:23][CH:22]([CH2:21][O:20][C:18]1[C:19]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:3][CH3:4])=[CH:10][CH:9]=3)=[C:12]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:13][C:14]=2[N:15]=[CH:16][N:17]=1)[C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(CO)C(C)(C)C)c23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(COCC(=O)OC(C)(C)C)C(C)(C)C)c23)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Add 0.5 ml of 11.25 N sodium hydroxide solution to a solution of 265 mg (0.62 mmol) 2-({[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)-3,3-dimethylbutan-1-ol in 10 ml toluene. After adding 21 mg (0.06 mmol) tetra-n-butylammonium hydrogensulphate and 240 mg (1.23 mmol) 2-bromoacetic acid tert.-butyl ester, stir the reaction mixture for 16 h at 70° C. After cooling to room temperature, neutralize with 1 N hydrochloric acid and extract with ethyl acetate. Wash the organic phase with satd. aqueous sodium chloride solution, dry over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 170 mg (51% of theor.) of the desired product (racemate) is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([NH:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=3[CH:16]=2)=[C:11]([N+:28]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.CO>[Zn].C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:28])[C:12]([NH:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=3[CH:16]=2)=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3[N+](=O)[O-])cc2s1
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3N)cc2s1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of 4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (2.8 g, 6.42 mmol) from the previous step, HOAc (7.5 mL), MeOH (7.5 mL) and DCM (50 mL) at 0° C. was added portionwise zinc dust (4.25 g, 65.4 mmol). The reaction mixture was stirred at 5° C. for 1 h. The mixture was filtered and the filtrate was diluted with DCM and washed sequentially with water and saturated aq NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-(benzyloxy)-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (2.49 g, 95%) as a light orange solid which was not purified further. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.26-7.44 (m, 7H), 6.59 (d, J=8.4 Hz, 1H), 6.46 (s, 1H), 6.38 (m, 1H), 4.97 (s, 2H), 4.34 (s, 2H), 3.54 (br s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][O:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23]CC)=[C:19]([Cl:26])[CH:18]=1)([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[OH-].[K+]>CN1CCN(C)C1=O>[O:1]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][O:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:26])[CH:18]=1)([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: CCOCC
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Yield: 50 %

Procedure:
With respect to the production of the compound of the formula (II), there is known only a process disclosed in Japanese Patent Application Kokai (Laid-Open) No. 212335/1987. The document discloses a process for producing 3-chloro-4-hydroxyneophyl m-phenoxybenzyl ether [a compound of the formula (II) wherein X1 =Cl and X2 =H] by subjecting 4-ethoxy-3-chloroneophyl m-phenoxybenzyl ether to an ether cleavage reaction. It is specifically a process comprising subjecting 4-ethoxy-3-chloroneophyl m-phenoxybenzyl ether to ether cleavage in N,N'-dimethylimidazolidinone, using excessive potassium hydroxide as an ether cleavage agent. According to the document, 4-hydroxy-3-chloroneophyl m-phenoxybenzyl ether was obtained under the reaction conditions of 150° C. and 18 hours, but the yield was as low as about 50%.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([CH2:12][C@H:13]([NH2:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[O:10]C.[BrH:16]>>[BrH:16].[OH:3][C:4]1[CH:5]=[C:6]([CH2:12][C@H:13]([NH2:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: COc1ccc(C[C@@H](C)N)cc1OC
Agent: Br
Agent: Cl
Product: C[C@@H](N)Cc1ccc(O)c(O)c1

Procedure:
A solution of (R)-3-(3,4-dimethoxyphenyl)-2-propylamine hydrochloride (500 mg, 2.15 mMol) in hydrogen bromide (48%, 5 ml) was stirred at 100° C. under an argon atmosphere for 20 hours. After cooling, the solvent was evaporated and the residue was dried giving the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=[O:26])[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(OC2CCN(c3ccccc3C=O)CC2)nc(-c2ccncn2)cc1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (1.00 g, 3.48 mmol) and 2-fluorobenzaldehyde (475 mg, 3.83 mmol) in dimethyl sulfoxide (3.50 ml) was added potassium carbonate (1.44 g, 10.4 mmol). The mixture was stirred at 120° C. for 4 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzaldehyde as a yellow solid (711 mg, 1.82 mmol, 52%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:51]([O:54][C:55]1[CH:62]=[CH:61][C:58]([CH:59]=O)=[CH:57][CH:56]=1)([CH3:53])[CH3:52]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:59][C:58]3[CH:61]=[CH:62][C:55]([O:54][CH:51]([CH3:53])[CH3:52])=[CH:56][CH:57]=3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccc(OC(C)C)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 18 %

Procedure:
The title compound was prepared by a similar method to example 5 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (225 mg, 0.46 mmol), sodium triacetoxyborohydnde (212 mg, 1.0 mmol) and 4-isopropoxybenzaldehyde (84 mg, 0.51 mmol) in tetrahydrofuran (15 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5). This gave the title compound (53 mg) as a foam. MS: 639 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:16]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[CH3:12].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[F:27][C:3]1[C:2](/[N:1]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:16]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[CH3:12]
Reactant: Cc1c(Cc2cccc(N)c2F)c(=O)oc2cc(Oc3nccs3)ccc12
Reactant: O=Cc1ccccc1
Solvent: CO
Product: Cc1c(Cc2cccc(/N=C\c3ccccc3)c2F)c(=O)oc2cc(Oc3nccs3)ccc12
Temperature: 25 °C

Procedure:
Methanol (4.0 mL) was added to 3-(3-amino-2-fluorobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran (compound 1h-3-4) (200 mg), and benzaldehyde (0.053 mL) was added to the resultant suspension while stirring at room temperature. The suspension was heated under reflux for 3 hours. The reaction solution was then cooled to room temperature, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel chromatography (amino gel) (dichloromethane) to yield the title compound (233 mg).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28]O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:32]3[C:33]2=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 66.8 %

Procedure:
2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (1.23 g), phthalimide (530 mg) and triphenylphosphine (1.10 g) were dissolved in tetrahydrofuran (15 mL) and stirred for 20 minutes. Diethyl azocarboxylate (0.57 mL) was then added to the solution, and it was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by chromatography (silica gel, 15-20% ethyl acetate:hexane) to give the title compound (1.08 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CC[O-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH3:17]
Reactant: Cc1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.4 g (53.6 mmol) 4-methyl-1H-imidazole are initially introduced into 20.0 ml (17.4 g, 53.6 mmol) 21% strength sodium ethylate solution in ethanol and 6.5 ml (9.8 g, 58.9 mmol) ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and the filtrate is concentrated in vacuo. The residue is purified by column chromatography over silica gel (mobile phase: acetonitrile/water 9:1). The product is obtained as a 3:2 mixture of the two regioisomers and is further reacted as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([F:14])[C:3]=1[NH2:15].[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:15][C:3]2[C:2]([F:1])=[CH:7][C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:5][C:4]=2[F:14])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Nc1c(F)cc(N2CCOCC2)cc1F
Solvent: CC#N
Product: O=C(CC1CCCC1)Nc1c(F)cc(N2CCOCC2)cc1F
Temperature: 150 °C
Yield: 75 %

Procedure:
2,6-Difluoro-4-morpholin-4-yl-phenylamine (0.20 g) and cyclopentylacetyl chloride (149 μL) were dissolved in acetonitrile (4 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo and purified by flash chromatography to furnish 228 mg (75%) of the title compound as a white solid. LC-MS (m/z) 325 (MH+); tR=2.61, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.19 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.74 (m, 2H), 2.19 (m, 1H), 2.26 (d, 2H), 3.14 (m, 4H), 3.70 (m, 4H), 6.68 (d, 2H), 9.20 (s, 1H).
Reaction SMILES: Cl.C(OC(=O)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:46])[CH2:20][N:21]2[N:27]=[C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]([CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:22]2=[O:45])[CH:13]=1)[CH2:9][CH2:10][CH3:11])(C)(C)C>O1CCOCC1>[CH:28]1([C:26]2[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]([CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:22](=[O:45])[N:21]([CH2:20][C:19]([NH:18][C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([NH:8][CH2:9][CH2:10][CH3:11])[CH:13]=3)=[O:46])[N:27]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCNc1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reaction time: 2 h
Yield: 91 %

Procedure:
4.0M HCl in dioxan (5 ml, 20.0 mmol) was added to a solution of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) (524 mg, 0.83 mmol) in dioxan (15 ml) at room temperature. The mixture was stirred for 2 h during which time a white precipitate formed. The solvent was evaporated, and the solid obtained was washed with Et2O, isolated by filtration and dried, to afford the hydrochloride salt of the title compound (430 mg, 91%). 1H NMR (CDCl3) 8.39 (1H, s), 7.61-7.27 (7H, m), 7.01 (1H, d), 4.69 (2H, br s), 4.60 (1H, d), 4.29 (2H, dd), 3.21 (2H, br s), 2.80 (1H, br s), 2.01-1.45 (6H, m), 1.43-1.19 (15H, m), 0.95 (3H, t). Found: C, 63.68; H, 7.65; N, 11.98%; C31H41N5O3.HCl.H2O requires: C, 63.52; H, 7.57; N, 11.95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(N(CC)C1C=CC=CC=1)C.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=O>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:24]=[C:25]([C:26]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 100 °C

Procedure:
The intermediate 2-(3-methylphenyl)benzimidazole was prepared by first mixing reacting 1-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene (180 ml) and heating to 100° C. To this mixture was then added 20 ml of N,N-diethylaniline and the reaction vessel was placed under a nitrogen atmosphere. To this solution was then added 3-methylbenzoyl chloride (24 ml, 132 mmol) and this mixture was then stirred overnight.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[B:11]([OH:13])[OH:12].[CH2:14](O)[CH2:15][CH2:16]O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[B:11]1[O:13][CH2:16][CH2:15][CH2:14][O:12]1
Reactant: OCCCO
Reactant: OB(O)c1ccc2c(c1F)OCO2
Solvent: Cc1ccccc1
Product: Fc1c(B2OCCCO2)ccc2c1OCO2
Yield: 93.4 %

Procedure:
2-Fluoro-3,4-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) was slurried in toluene and propane-1,3-diol (0.6 g, 7.9 mmol) and the mixture heated under reflux for 0.5 hour. The mixture was cooled, filtered through glass wool and concentrated to give 2-(2-fluoro-3,4-methylenedioxyphenyl)-[1,3,2]-dioxaborinane (1.6 g, 7.1 mmol): 1H NMR (DMSO-d6): δ 7.12 (dd, 1H, J=7.8, 5.7 Hz), 6.75 (d, 1H), 6.09 (s, 2H), 4.06 (t, 4H), 1.98 (m, 2H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>[Cu]I>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:45][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Sc1ccccc1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: c1ccc(Sc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 120 °C

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.125 g, 0.334 mmol), Sodium tert-butoxide (96.4 mg, 1.00 mmol), Copper(I) iodide (6.4 mg, 0.033 mmol), 1,2-Ethanediol (37.4 uL, 0.671 mmol), N,N-Dimethylformamide (4.7 mL, 6.0E1 mmol), and finally Benzenethiol (51.4 uL, 0.501 mmol). The reaction was heated at 120° C. overnight. The reaction was partitioned with DCM and water. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol) the collected fractions afforded (4-Morpholin-4-yl-phenyl)-(7-phenylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine an orange solid (72 mg, 53%). MP 143-145° C. LCMS (E/I+) 404.17 (M+H). NMR 1H (DSMO-d6)-9.33 (s, 1H), 8.97 (s, 1H), 7.45 (d, 2H, J=9.05 Hz), 7.30 (t, 2H, J=7.57 Hz), 7.18 (t, 1H, J=7.29), 7.12 (d, 2H, J=7.37 Hz), 7.01 (d, 1H, J=4.40 Hz), 6.93 (d, 1H, J=4.60 Hz), 6.75 (d, 2H, J=9.05 Hz), 3.73 (t, 4H, J=4.48 Hz), 3.00 (t, 4H, J=4.72 Hz).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([CH3:31])[CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1>[H-].C([Al+]CC(C)C)C(C)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[CH:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:29])[F:30])=[C:23]([CH3:31])[CH:22]=3)[NH:13]2)=[O:11])=[CH:7][CH:8]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OC(F)F)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)NC1c1ccc(OC(F)F)c(C)c1
Yield: 57.7 %

Procedure:
By substantially following the procedure given in Example 19i using 1.0 g (2.2 mmole) of N-(4-trifluoromethylphenyl)-3-(4-difluoromethoxy-3-methylphenyl)-4-propylamino-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 29b) and 10 ml of 1.0M diisobutylaluminum hydride one obtains 0.6 g of N-(4-trifluoromethylphenyl)-3-(4-difluoromethoxy-3-methylphenyl)-4-propylamino-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide, an oil. NMR 0.9 t 3H, 2.5 m 2H, 2.3 s 3H, 2.6 t 2H, 3.5 bd 2H, 3.7 m 1H, 4.0 m 2H, 4.8 bm 1H, 6.4 t 1H, 7.1 m 3H, 7.4 m 4H, 8.3 s 1H.
Reaction SMILES: [F:1][CH:2]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:14]I>O1CCCC1>[F:1][C:2]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([C:3](=[O:8])[C:4]([CH3:7])([CH3:5])[CH3:6])[CH3:14]
Reactant: CI
Reactant: CC(C)(C)C(=O)C(F)n1cncn1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(C)(F)n1cncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
20.0 g of 1-fluoro-1-(1H-1,2,4-triazol-1-yl)-3,3-dimethyl-2-butanone are added dropwise to a solution of 13.5 g of potassium tertiary butylate in 100 ml of tetrahydrofuran. After the mixture has been stirred for 0.5 hour, 15.6 g of methyl iodide are added dropwise and the mixture is stirred for 18 hours at 60° C. After cooling, the reaction mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Distillation of the oily residue gives 14.0 g of 2-fluoro-2-(1H-1,2,4-triazol-1-yl)-4,4-dimethyl-3-pentanone, boiling point 48°-50° C./0.013 mbar.