Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1/[C:16](=[N:18]/[S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])/[CH3:17]>C1COCC1.[Zn].[Cu]Cl>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C@@:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[F:8])([NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH3:17])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A dried four-necked 750 ml round-bottom flask equipped with mechanical stirrer, reflux condenser, internal thermometer and septum was charged with activated zinc powder (30.6 g, 468 mmol) and copper(I) chloride (4.64 g, 47 mmol), the two solids were mixed under a slow stream of nitrogen while the flask was dried with a heat gun. After cooling to 23° C., dry THF (90 ml) was added to produce a dark slurry, heated to reflux and stirred vigorously for 30 min. The heating bath was removed and a solution of ethyl bromoacetate (12.95 ml, 117 mmol) in dry THF (50 ml) was added at such rate that reflux was reinitiated and a controllable reflux was maintained. Once addition was complete, the mixture was stirred for 30 min at 50° C. Cooled to 5° C., a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-5-bromo-phenyl)-(E)-ethylidene]-amide (intermediate A2B) (15.0 g, 47 mmol) in dry THF (60 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered through dicalite, washed with TBME, the filtrate was washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the crude title compound as an orange oil (20.3 g, 106%), which was used in the next step without further purification. MS (ISP): m/z=408.0 [(M+H)+] and 410.1 [(M+2+H)+].
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48](O)=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].Cl[C:53]([N:57]([CH3:59])C)=C(C)C.C(OC(C)(C)C)(=O)[NH:61][NH2:62].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:15][C@H:16]([CH2:47][C:48]3[N:57]([CH3:59])[CH:53]=[N:62][N:61]=3)[NH:17][CH2:18][C@@H:19]2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](Cc3nncn3C)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.0 mmol of [(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) -piperidin-2-yl]-acetic acid (example 1g) in 5 ml of CH2Cl2 is treated at RT with 1.5 mmol of 1-chloro-N,N,2-trimethylpropenylamine, and stirred at RT for 2.5 h. This solution is added slowly, at 0° C., to a solution of 5 mmol of tert-butyl carbazate [870-46-2] and 5 mmol of Et3N in 1 ml of CH2Cl2. The reaction mixture is stirred at 4° C. for 16.5 h, then quenched with H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[O:34][C:35]4[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:36]=4[N:37]=3)=[CH:28][CH:27]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]3)[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]4[O:34][C:35]5[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:36]=5[N:37]=4)=[CH:30][CH:31]=3)[C:10]=12
Reactant: CN1CCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-N2-{4-[4-Amino-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from rac-3-iodo-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.581 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.265 g, 0.726 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.062 g, 23%). 1H NMR (DMSO-d6, 400 MHz) 2.39 (s, 3H), 2.32-2.40 (m, 3H), 2.40 (s, 3H), 2.75-2.80 (m, 2H), 3.08 (t, 1H), 3.26 (s, 3H), 5.40 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.85 (s, 1H); RP-HPLC Rt 10.905 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 455 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1Cc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2Cc2ccccc2)c1Br
Yield: 24 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 by reacting 2-chlorosulfonyl-3-benzylthiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 24% yield, m.p. 180-183° C.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[S:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:20][C:21](=O)[NH:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([O:31][CH3:32])[N:24]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:30][O:29][C:27]1[N:26]=[C:25]([O:31][CH3:32])[N:24]=[C:23]([NH:22][C:21]([NH:14][S:11]([C:10]2[C:5]3[S:4][CH2:3][CH2:2][S:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:12])=[O:13])=[O:20])[N:28]=1
Reactant: NS(=O)(=O)c1cccc2c1SCCS2
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(NC(=O)NS(=O)(=O)c2cccc3c2SCCS3)nc(OC)n1
Temperature: 25 °C

Procedure:
To a solution of 2.5 g 1,4-benzodithian-5-sulfonamide, prepared in Example 16, in 50 ml methylene chloride at ambient temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature 2.0 g of methyl[4,6-Dimethoxy-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 3 is added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid, and 10 drops hydrochloric acid are sequentially added. The organic phase is separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from an appropriate organic solvent gives a solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]1[C:17]([O:19][CH3:20])=[O:18])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:30].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[OH:30][CH2:3][CH2:2][CH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH:5]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: [OH-]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl 3-methyl 4-allylpiperidine-1,3-dicarboxylate [WO2002/072572] (715 mg, 2.53 mmol) in tetrahydrofuran (5 mL) at 0° C. was treated with a solution of 9-BBN in tetrahydrofuran (0.5M, 10.2 mL, 5.1 mmol). After one hour the reaction mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was cooled to 0° C. and treated with water (3 mL), NaOH (3N, 6 mL) and hydrogen peroxide (30% solution, 6 mL). The reaction was allowed to warm to room temperature and stir for one hour. The reaction was diluted with ethyl acetate and water. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated at reduced. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave the product as a colorless oil as a mixture of diastereomers (460 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1C=C.C[N+]1([O-])[CH2:16][CH2:15][O:14]CC1.[OH2:18]>C(#N)C.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]([OH:14])[CH2:16][OH:18]
Reactant: O
Reactant: C=Cc1ccccc1Br
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: OCC(O)c1ccccc1Br
Reaction time: 24 h

Procedure:
To a stirred solution of 1-bromo-2-vinylbenzene (4.14 g, 22.6 mmol) and 4-methylmorpholine N-oxide in acetonitrile (20 mL) and water (10 mL) was added a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol (2 mL) at room temperature and the mixture was stirred for 24 h at the same temperature. The reaction mixture was quenched by the addition of sodium hydrosulfate, and diluted with water, then extracted with ethyl acetate. The organic layer washed with diluted hydrochloric acid aqueous solution and brine, dried over sodium sulfate, and evaporated to afford 5.01 g (quant.) of the title compound as a brown solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:49][CH3:50])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH:42](OCC)OCC)=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:51][CH3:52])[N:27]=1.Cl.[CH3:54][O:55][NH2:56].Cl.C1(C)C=CC=CC=1>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:49][CH3:50])[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH:42]=[N:56][O:55][CH3:54])=[CH:38][CH:39]=2)[CH:29]=[C:28]([CH2:51][CH3:52])[N:27]=1
Reactant: CON
Reactant: CCOC(COc1ccc(C(CC)Nc2cc(CC)nc(Cl)n2)cc1)OCC
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1cc(NC(CC)c2ccc(OCC=NOC)cc2)nc(Cl)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 1.0 g of dl-5-chloro-6-ethyl-4-[α-ethyl-4-(2,2-diethoxyethoxy)benzyl]aminopyrimidine obtained in Example 19 dissolved in 40 ml of ethanol was added 0.4 g of methoxyamine hydrochloride. Then, after addition of a catalytic amount of a 6N hydrochloric acid, the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and extracted with ethyl acetate. Then, the extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene: ethyl acetate=7:1) to give 0.4 g of the desired product as pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O1CCOCC1.CCN(C(C)C)C(C)C>CO.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=c1sc2cc(Br)ccc2n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a round bottom flask was added 6-bromo-1,3-benzothiazol-2(3H)-one (0.050 g, 0.217 mmol), copper(2+) diacetate (0.079 g, 0.435 mmol), [3-(trifluoromethyl)phenyl]boronic acid (0.124 g, 0.652 mmol), Dioxane (1 mL), and DIPEA (0.114 mL, 0.652 mmol). The reaction mixture was then permitted to stir open to the atmosphere for ˜17 hours (overnight). The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 30% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 6-bromo-3-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2(3H)-one (15-1) as a white solid. HRMS (M+H)+: observed=373.9455, calculated=373.9457.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:31](=[O:33])[CH3:32])[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 43 %

Procedure:
A solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine (19.3 mg, 0.044 mmol, 1 eq.) in 1 mL of acetic anhydride and 1 mL of pyridine was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 9 mg (43%) of desired 1(4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidin-1-yl)ethan-1-one. Compound was determined to be 95% pure by 1H NMR. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.52 (m, 2 H) 2.03-2.27 (m, 5 H) 2.81 (t, J=11.49 Hz, 1 H) 3.13-3.33 (m, 1 H) 3.81 (d, J=13.75 Hz, 1 H) 4.41 (br. s., 1 H) 4.55 (d, J=13.66 Hz, 1H) 5.78 (br. s., 1 H) 7.00-7.55 (m, 8 H) 8.37 (s, 1 H), [M+Na]+ 503.8.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@@H:4]2[C@H:7]([CH:8]=1)[C@@:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:9][N+:10]([O-])=O)[CH2:5]2.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:10][CH2:9][C@@:6]1([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C@H:4]2[C@@H:7]1[CH:8]=[C:2]([CH3:1])[CH2:3]2
Reactant: CC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-methyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.12 g, 3.99 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (892.8 mg, 15.9 mmol) and ammonium chloride (211.5 mg, 3.99 mmol) were added, and the mixture was stirred for 4 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (105.8 mg, 28%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:26][CH2:27][OH:28])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a solution of benzhydryl piperazine (7.28 gm) in toluene (35 ml) at room temperature, dimethyl formamide (70 ml), 2-chloroethanol (5 ml) and potassium carbonate (5 gm) were added. The reaction mass was heated to reflux with constant stifling for 14-16 hours. Reaction mass was cooled, filtered, and concentrated under vacuum to get 2-(4-benzhydryl piperazine-1-yl) ethanol (yield: 7.5 gm).
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([O:15][C:6]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]=1[O:2][CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[O-]
Reactant: Fc1ccc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1OCc1ccccc1

Procedure:
A solution of sodium methoxide in methanol (25% wt, 20 ml) and the product from step (i) (1.20 g) was heated at 100° C. for 3 h. The mixture was quenched with water (100 ml) and the solid was filtered and dried, yield 1.28 g.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[F:21][C:22]([F:34])([F:33])[C:23]1[NH:24][C:25]2[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:32][C:30]4[CH:29]=[CH:28][C:26]5[N:27]=[C:23]([C:22]([F:34])([F:33])[F:21])[NH:24][C:25]=5[CH:31]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)cn1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.2 mmol) was coupled to 2-trifluoromethyl-3H-benzimidazol-5-ylamine (72 mg, 0.36 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 32 mg (30%) of tan powder; LC/MS: 426 (M+H); HPLC: 97% pure, RT=3.06 min; 1H NMR: (DMSO, δ) 9.64 (s, 1H), 9.02 (s, 1H), 8.97 (d, J=2.0, 1H), 8.56 (dd, J=8.8, 2.5, 1H), 8.12 (s, 1H), 7.66 (m, 2H), 7.22 (d, J=4.9, 1H), 7.01 (d, J=8.8, 1H), 6.99 (d, J=4.9, 1H), 3.94 (s, 3H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1=[O:21])[CH3:2].[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:12][C:11]1[C:6]2[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:4](=[O:21])[N:3]([CH2:1][CH3:2])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(C)cccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reaction time: 0.5 h

Procedure:
The mixture of 1.00 g of 1-ethyl-4-methyl-3-(2-trimethylsilanylethoxymethyl)-1,3-dihydrobenzimidazol-2-one, 0.469 g of N-bromosuccinimide, 0.025 g of 2,2′-azobis(2-methylpropionitrile) and 0.037 g of dibenzoyl peroxide in 60 ml of carbon tetrachloride is heated to reflux with stirring. The reaction vessel is irradiated with a 150 W lamp over the reaction time. After 0.5 hour, the reaction mixture is cooled and filtered through Hyflo. The filtrate is concentrated. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (40:1 dichloromethane-diethyl ether); Rt=5.80.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:15][C:16](=[O:25])[C@@H:17]([O:21][C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][OH:20])[CH3:14].[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:15][C:16](=[O:25])[C@@H:17]([O:21][C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][O:20][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:14]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)[C@H](CCO)OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCOc1ccccc1)OC(C)=O
Yield: 99.2 %

Procedure:
Diethyl azodicarboxylate (1.37 g, 7.9 mmol) in tetrahydrofuran (3 ml) was added to a stirred mixture of (S)-2-acetoxy-4-hydroxybutanoic acid ethyl ester (1.0 g, 5.3 mmol), phenol (0.74 g, 7.9 mmol) and triphenylphosphine (2.07 g, 7.9 mmol) in tetrahydrofuran (16 ml). After 4 days the solvent was evaporated and the residue purified by chromatography on silica with ethyl acetate/petroleum ether (60°-80°) mixtures as eluant, to give the sub-title compound (1.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2.[F:25][C@@H:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27]O>>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH2:27][C@@H:26]([F:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2
Reactant: CCCCCC[C@H](F)CO
Reactant: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(O)ccc12
Product: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(OC[C@@H](F)CCCCCC)ccc12

Procedure:
From 9-fluoro-7-octylphenanthren-2-ol by reaction with 2-(S)-fluorooctan-1-ol by Mitsunobu reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=CCCc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Brc1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.03 g (4.82 mmol) 3-(4-bromo-phenyl)-propionaldehyde and 0.41 mL (4.82 mmol) pyrrolidine in 50 mL MeOH is adjusted to pH 4-5 with glacial acetic acid. Then 400 mg (6.05 mmol) NaBH3CN are added batchwise and the reaction is stirred for 3 days at RT. The reaction solution is diluted with 30 mL water and the aqueous phase is extracted with 50 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 9:1:0.1).