Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: Brc1ccc(Br)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc(Br)ccc1Br
Temperature: 90 °C
Yield: 79 %

Procedure:
A modification of the published procedures of Moroni et al. in Macromolecules 1994, 27, 562 was used. A 300 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 1,4-dibromobenzene (50 g, 0.21 moles) and chlorosulfonic acid (100 mL). The mixture was heated to 90° C. for 2 hours under nitrogen to give a clear solution. The solution was cooled to room temperature and carefully poured onto ice (1 kg) to give a precipitate. The solids were collected by vacuum filtration, washed well with water, and air dried on the filter then dried under vacuum at 50° C. to give 68.36 g. The product was recrystallized from cyclohexane after treating with decolorizing carbon, collected by vacuum filtration, and dried at 50° C. under vacuum to give 55.37 g (79% yield) of 2,5-dibromobenzenesulfonyl chloride. 1H NMR (CDCl3): 7.66 (dd, 8.4, 2.3 Hz, 1H), 7.72 (d, 8.4 Hz, 1H), 8.30 (d, 2.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CC(N(C)C)=O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Yield: 38.5 %

Procedure:
A mixture of 4-hydroxybenzoic acid (3.50 g, 25 mmol), 4-fluorobenzonitrile (3.00 g, 35 mmol), and powdered K2CO3 (6.80 g, 49 mmol) were heated in DMAC (50 mL) at 140° C. for 20 hours. The cooled mixture was then acidified with 1N HCl and extracted with EtOAc (3×50 mL). Concentration of the extracts in vacuo left a residue which was chromatographed over silica gel (5% MeOH/CHCl3) to provide 2.30 g (39%) of pure product. MS (FD+) 238.9
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=2[F:37])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:39]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:39].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=1[F:37]
Reactant: Fc1cc(Br)ccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1C(F)(F)F
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: Fc1cc(Br)ccc1C(OC1CNC1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydryloxy]azetidine (113) (15 mmol) using the procedure described for compound (9) (2.26 g, 51%).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]2.[H-].[Na+].CI.[CH:25](OC(C)(C)C)=O>CN(C)C=O.O.C(OCC)(=O)C>[CH3:25][O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]2
Reactant: CC(C)(C)OC=O
Reactant: COc1ccc2c(c1O)CCN(C(=O)OC(C)(C)C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (100 mg, 0.36 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) and sodium hydride (12.9 mg, 1.50 equiv). This was followed by the addition of CH3I (254.2 mg, 5.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 85 mg (81%) of tert-butyl 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate as a light yellow solid. MS (ESI) m/z 194 ([M+H-t-Boc]+); Rf 0.28 (starting material) and 0.43 (product) in ethyl acetate:petroleum ether=1:3.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1(C2CCNCC2)C[CH2:35][CH2:34]1>>[N:8]1([CH:9]2[CH2:35][CH2:34][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:11][CH2:10]2)[CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Reactant: C1CN(C2CCNCC2)C1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-azetidin-1-yl-piperidine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a cream solid (54 mg, 66%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:23]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[OH:24])[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: Brc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C(O)c2nccs2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-BuLi (1.9 mL, 2.5 M in hexane) in ether (8 mL) at −78° C. is added 2-bromothiazole (0.34 mL, 3.80 mmol) dropwise. The yellow solution is stirred at −78° C. for 30 min and 3-benzyloxy-4-nitrobenzaldehyde (83, step A) (0.81 g, 3.16 mmol) in THF (2 mL) is added. After stirring for 30 min, the purple suspension is poured into a sat. NH4Cl solution (50 mL) and is extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is then purified by column chromatography to give the title compound: (M+1)+=343.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>C1COCC1.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]([F:20])([F:33])[F:32])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: OB(O)c1ccccc1OC(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1nc(-c2ccccc2OC(F)(F)F)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (3.5 g, 7.7 mmol), 2-trifluoromethoxyphenylboronic acid (2.2 g, 7.7 mmol), dichloro[1,1′bis(diphenyl-phosphino) ferrocene]palladium(II) dichloromethane adduct (284 mg, 0.4 mmol) in THF/Acetonitrile/saturated NaHCO3 (25 ml/25 ml/30 ml) was stirred at 60° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-(2-trifluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (2.2 g, 59% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.94 (m, 2H), 3.77 (m, 2H), 6.00 (s, 2H), 7.75 (m, 2H), 7.80 (d, 1H), 8.01 (d, 1H), 8.66 (s, 1H), 8.91 (s, 1H). MS: m/z 489.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.[BH4-].[Na+].Cl>C(O)C.ClCCl.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccnc1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Nc2ncc(CNc3cccnc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 18.1 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (153.3 mg, 0.3441 mmol) was suspended in ethanol (3.0 mL) and dichloromethane (3.0 mL), 3-aminopyridine (65.9 mg, 0.700 mmol) and tetraisopropoxytitanium (0.15 mL, 0.51 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (50° C.-60° C.) and stirred under nitrogen for 6 hours. Then, the reaction was cooled to room temperature and allowed to stir overnight. After stirring overnight, sodium borohydride (26.7 mg, 0.706 mmol) was added, and stirring was continued at room temperature. After 35 minutes, the reaction was treated with 5 N HCl (0.60 mL) added dropwise, as gas evolution occurs. The reaction was diluted with MeOH (about 1 mL, both before and after adding the HCl) and stirred at room temperature for 5 hours. Then, the reaction flask was fitted with a reflux condenser and put in an oil bath which was heated to 50° C. Stirring was continued at this temperature for 1 hour, and then the reaction was cooled to room temperature. The suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and treated with water and filtered. The solid was collected and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-3-ylamino)methyl)pyridin-2-amine (27.3 mg, 18%). MS (ESI pos. ion) m/z 440 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.63 (br s, 1H), 12.59 (s, 1H), 9.79 (s, 1H), 8.57 (s, 1H), 8.54 (d, J=2.74 Hz, 1H), 8.35 (d, J=2.35 Hz, 1H), 8.19-8.10 (m, 2H), 8.04 (d, J=1.56 Hz, 1H), 7.75-7.68 (m, 2H), 7.57 (br s, 1H), 6.85 (d, J=8.80 Hz, 1H), 4.45 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:40]=[CH:39][C:31]([O:32][CH2:33][C:34]([O:36]CC)=O)=[CH:30][CH:29]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH3:42].CO>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([NH2:42])=[O:36])=[CH:39][CH:40]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(=O)OCC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Reactant: N
Solvent: CO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(N)=O)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 70 °C
Reaction time: 43 h
Yield: 35 %

Procedure:
Ethyl (4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate (300 mg) was added to a 7N ammonia-methanol solution (15 ml) and then stirred at 70° C. for 43 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:1→9:1→ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane, giving a pale yellow powder of 2-(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetamide (100 mg, yield: 35%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[I-:29].[Na+].I>CC(CC)=O.O1CCOCC1>[I:29][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cc(C)nc(Cl)c3)nc12
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCC(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cc(C)nc(I)c3)nc12
Temperature: 100 °C
Yield: 6.6 %

Procedure:
To a stirred suspension of 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-methyl-isonicotinamide (1.00 g, 2.39 mmol) in ethyl methyl ketone (10 ml) and dioxane (20 ml) were added sodium iodide (2.0 g, 13.3 mmol) and hydriodic acid (0.95 ml, 7.2 mmol, 57% aqueous). The mixture was then heated at 100° C. for 96 hours. The mixture was then concentrated in vacuo and the residue resuspended in dichloromethane and washed sequentially with saturated sodium bicarbonate solution, 0.1 M sodium thiosulfate solution, and saturated brine. The organic phase was then dried over Na2SO4 and the solvent evaporated. The crude product was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2MeOH (99:1 then 98:2), the product fractions were pooled and the solvent evaporated, to afford the title compound as a brown solid (80 mg, 7% yield), MS: m/e=511 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[CH:45][CH:44]=2)[C:20]([N:22]([CH2:32][C:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[S:36][CH:37]=2)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 76 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([CH3:22])[C:12](=[O:19])[CH:11]=1
Reactant: CI
Reactant: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-5-nitropyridin-2(1H)-one (1.28 g, 3.41 mmol) was dissolved in dry DMF (20 mL) and cooled to 0° C. under an ice-bath. To the solution was added NaH (60% in oil) (168 mg, 4.2 mmol) portion-wise. The resulted mixture was stirred at 0° C. for 1 hour, followed by the addition of methyl iodide (260 uL, 4.17 mmol) drop-wise through a syringe. The solution was allowed to warm to room temperature and stirred for 16 hours. Water (20 mL) was added slowly and stirring was continued for 30 minutes. The resulted yellow precipitate was filtered, dried under vacuum at 40° C. for 5 hours, and used for the next reaction without further purification. (1.017 g, 77% yield)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1=S
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
To 50 ml of an ethanol solution of 1.70 g (5.13 mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione (isomer A) was added 14 ml of Raney nickel, followed by stirring at room temperature for 1.5 hours. Any insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and the mixture was washed with 10% aqueous ammonia. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.479 g (95.7%) of the title compound (isomer A) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]([OH:19])[CH3:18]>O=[Mn]=O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Agent: O=[Mn]=O
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C

Procedure:
To a solution of 1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (see Preparation 2)(4.40 g, 15.4 mmole), is added MnO2 (7.88 g, 77.0 mmole) in one portion. The mixture is heated under reflux for 16 hours, more MnO2 (7.88 g, 77.0 mmole) is added to the reaction and continued to reflux for 4 hours. The mixture is filtered through a celite pad, and the mother liquid is concentrated. The crude product is purified on a silica gel column, gradient eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:15]([CH2:34][O:35][CH3:36])[O:14]2)=[C:6]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:5]=1.[CH:52]1([CH:55]=O)[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Si:19]([O:18][C@@H:17]1[C@H:16]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28])[C@@H:15]([CH2:34][O:35][CH3:36])[O:14][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:4]([CH2:3][CH2:2][NH:1][CH2:55][CH:52]1[CH2:54][CH2:53]1)=[N:5][C:6]=2[NH:37][CH2:38][CH:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: O=CC1CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
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(CCNCC4CC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 78.8 %

Procedure:
The title compound was prepared by a similar method to example 5 from N-{2-(2-aminoethyl)-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-9H-purin-6-yl)-N-(2,2-diphenylethyl)amine (430 mg, 0.58 mmol) (preparation 18), cyclopropanecarbaldehyde (45 mg, 0.64 mmol) and sodium triacetoxyborohydride (270 mg, 1.27 mmol) in tetrahydrofuran (10 ml). The product was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane rising in polarity to dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (360 mg) as a gum. MS: 788 (MH+).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[CH:10][NH:9][N:8]=2)=[CH:3][CH:2]=1.[F:13][C:14]([O:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)([F:19])[C:15]([F:18])([F:17])[F:16].C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2.Cl>CN(C=O)C.O.[Cu]I.CCOCC.O>[F:13][C:14]([F:19])([O:20][C:21]1[CH:22]=[CH:23][C:24]([N:9]2[CH:10]=[N:11][C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=3)=[N:8]2)=[CH:25][CH:26]=1)[C:15]([F:16])([F:18])[F:17]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(Br)cc1
Reactant: Cc1ccc(-c2nc[nH]n2)cc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 130 °C
Yield: 62.1 %

Procedure:
A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 50 mL of 9:1 DMF/H2O was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with 100 mL of hexanes. The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 7.0 g (61% based on starting triazole) of 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole as an off-white solid, mp 130-132° C.; ESIMS 370.8 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](N)=[NH:20].CC[O-].[Na+].O>CN(C=O)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:20][C:9]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=3)=[N:11][N:12]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: N=C(N)c1cccc(N)c1
Reactant: NNC(=O)c1nc(Br)cnc1N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2nnc(-c3nc(Br)cnc3N)[nH]2)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carbohydrazide (5 g, 21.55 mmol), 3-aminobenzamidine dihydrochloride (4.484 g, 21.55 mmol) and NaOEt (4.399 g, 64.65 mmol) were combined in DMF (50.00 mL) and heated to 100° C. in the microwave for 20 min. Water was added and the precipitate collected. Used without further purification. Assumed 100% Yield.