Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CCl
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Cool a suspension of 2-bromo-4-fluoro-phenol (1 g, 4.89 mmol) and K2CO3 (1.8 g, 13.2 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add chloroacetone (678 mg, 7.33 mmol) during a period of 30 min. Stir the mixture at RT overnight. Add water and extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to give the title compound as a yellow oil (0.75 g, 59%). 1H NMR (400 MHz-CDCl3) δ 2.35 (s, 3H), 4.51 (s, 2H), 6.73 (dd, J=4.8, 8.8 Hz, 1H), 6.97 (m, 1H), 7.32 (m, 1H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9].C[O-].[Na+].Cl>O>[CH3:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8]([O:3][CH2:2][CH2:1][OH:4])=[O:9]
Reactant: OCCO
Reactant: CCOC(=O)CN(C)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)OCCO)c1ccccc1
Temperature: 150 °C
Reaction time: 13 h

Procedure:
Into a 100 ml. flask fitted with a condenser and a Dean-Stark trap there were placed 49.5 gms. ethylene glycol, 17 gms. of ethyl N-methyl-N-phenylglycinate and 0.7 gm. sodium methoxide. The flask and contents were heated to 150° C. in an oil bath and stirred for 13 hours. The reaction mixture was allowed to cool to room temperature and 1.25 ml. of concentrated HCl in 3.5 ml. water were added and the mixture was stirred for 10 minutes. After the ethylene glycol was distilled off at atmospheric pressure, 11.5 gms. of product was obtained by vacuum distillation, b.p. (0.3 mm.) 139°-149° C.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([N:26]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH2:27][CH3:28])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:46]1(B(O)O)[CH2:48][CH2:47]1>C(=O)([O-])[O-].[K+].[K+].C1COCC1.O>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([N:26]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH2:27][CH3:28])=[CH:24][CH:23]=[C:22]([C:46]([CH3:48])=[CH2:47])[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)c1ccc(N(CC)C[C@H]2CC[C@H](CC(=O)OCC)CC2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 85 °C

Procedure:
A mixture of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate, cyclopropylboronic acid and 1,1′-bis(di-t-butylphosphinoferrocene) palladium dichloride in 1N aqueous potassium carbonate and THF was heated at 85° C. in a sealed tube overnight. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropenylpyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. Rf=0.44 (20% EtOAc/hexanes). LCMS calc.=670.3; found=670.4 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 7.87 (s, 1 H); 7.78 (s, 2 H); 7.40 (s, 2 H); 5.85 (s, 1 H); 5.75 (d, J=8.6 Hz, 1 H); 5.25 (s, 1 H); 4.96 (d, J=16.7 Hz, 1 H); 4.42-4.36 (m, 2 H); 4.08 (q, J=7.1 Hz, 2 H); 2.98-2.92 (m, 2 H); 2.85 (dd, J=6.5, 13.0 Hz, 1 H); 2.76 (dd, J=7.5, 13.0 Hz, 1H); 2.20 (s, 3 H); 2.12 (d, J=6.8 Hz, 2 H); 1.83-1.65 (m, 5 H); 1.36-1.30 (m, 1 H); 1.22 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.0 Hz, 3 H); 0.95-0.83 (m, 4 H); 0.72 (d, J=6.7 Hz, 3 H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=2[S:5][CH:4]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:16][CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=2[S:5][CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: Clc1ncnc2c(CBr)csc12
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc2c(Cl)ncnc12
Temperature: 35 °C
Reaction time: 4 h

Procedure:
7-(Bromomethyl)-4-chlorothieno[3,2-d]pyrimidine (9.17 g, 33.0 mmol) was dissolved in DMF (54 mL) and then sodium acetate (27 g, 330 mmol) and potassium iodide (10.96 g, 66.0 mmol) were added thereto. The reaction mixture was stirred at 35° C. for 4 hours, diluted with ethyl acetate and washed with sat. sodium thiosulfate solution 5 times. The reaction mixture was dried with MgSO4, filtered, concentrated and purified by silica gel chromatography to obtain to obtain the title compound as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[NH:8][C@@H:7]([CH3:9])[CH2:6][N:5]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:4]1.[BH3-][C:19]#N.[Na+].C=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[CH3:9][C@H:7]1[N:8]([CH3:19])[C@@H:3]([CH3:2])[CH2:4][N:5]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6]1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2)C[C@H](C)N1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)cc2)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
4-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-benzonitrile hydrochloride (1 g, 3.97 mmol) was dissolved in DCM (25 ml) and TEA (1.1 ml, 7.94 mmol). NaBH3CN (374 mg, 5.96 mmol) and CH2O (37% water solution, 0.446 ml, 5.96 mmol) were added to the resulting solution. The slurry was stirred overnight at room temperature, then further CH2O (0.297 ml, 3.97 mmol) and NaBH3CN (249 mg, 3.97 mmol) were added. The slurry was stirred at room temperature for 4 h, then brought to basic conditions with 5% NaHCO3 and extracted twice with DCM. The collected organic phases were dried over Na2SO4 and evaporated in vacuo. The resulting oil was taken up with DCM and treated with HCl/Et2O. The precipitate was filtered and washed with di-isopropylether to give 1 g of 4-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-benzonitrile hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccccc1CCl
Product: COc1ccccc1CC1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 30.2 %

Procedure:
With 4.50 g of 2-methoxybenzyl chloride and 4.34 g of 5-chloroisatin as starting materials, 2.19 g of the title compound (orange red solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(O)C.C1CCCCC=1>[Pd].O>[CH3:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ccc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc2[nH]ccc12

Procedure:
4.3 g of nitro derivative prepared in stage 3, 20 ml of ethanol, 9 ml of cyclohexene, 3 ml of water and 2.2 g of 10% palladium on carbon are mixed and are then heated to reflux for 2 hours.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCI
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of triphenylphosphine (40 g, 153 mmol) and imidazole (10.4 g, 153 mmol) in CH2Cl2 (375 mL) at RT, is added iodine (40.8 g, 160.6 mmol) portionwise. To this solution is added (2-hydroxyethyl)-carbamic acid tert-butyl ester (24.2 g, 150 mmol) in CH2Cl2 (75 mL) dropwise and the mixture allowed to stir at RT for 14 h. The mixture is then filtered and the filtrate concentrated to a crude red oil, which is partitioned between ether and sat. sodium thiosulfate. The aqueous phase is extracted with ether. The combined organic layers are reduced to 500 mL and then filtered through a plug of silica, eluting with hexane. Evaporation of solvent affords the title compound.
Reaction SMILES: C1(COC([NH:11][C@H:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[CH2:15][N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]2=[O:29])=O)C=CC=CC=1.CO.C(Cl)Cl.C(Cl)(Cl)Cl>[OH-].[OH-].[Pd+2].C(O)C>[NH2:11][C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29]
Reactant: CCOC(=O)CN1Cc2ccccc2C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CN1Cc2ccccc2C[C@H](N)C1=O
Reaction time: 2 h

Procedure:
20% Palladium hydroxide/carbon catalyst was added to a solution of (S)-1,3,4,5-tetrahydro-4-[[(phenylmethoxy)carbonyl]amino]-3-oxo-2 H-2-benzazepine-2-acetic acid, ethyl ester (1.037 g., 2.62 mmole) in absolute ethanol (20 ml.) and the resulting suspension was stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered through Celite and filtrate was evaporated to dryness. The semi-solid residue was triturated with hexane to give 0.63 g. of product as a white, crystalline solid; m.p. 71°-73° C.; Rf =0.38 (methanol:methylene chloride, 1:9); [α]D =77.5° (c=0.59, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[F:16])[CH2:5][C:6]#[N:7].Cl>CO.[Pt](=O)=O>[ClH:15].[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[F:16])[CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)C(CC#N)c1c(F)ccc(Cl)c1F
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCN)c1c(F)ccc(Cl)c1F
Reaction time: 3.5 h

Procedure:
To a solution of 2-(3-Chloro-2,6-difluorophenyl)-3-cyanopropionic acid methyl ester (784 mg, 3.0 mmol) and concentrated hydrochloric acid (0.63 mL, 7.55 mmol) in MeOH (5 mL) was added platinum dioxide (69 mg, 0.3 mmol) under nitrogen. The reaction mixture was degassed (5× vacuum cycles) and the nitrogen atmosphere replaced with hydrogen (5× vacuum cycles). The mixture was stirred for 3.5 hours, then filtered through a pad of Celite®, washing with MeOH. The filtrate was concentrated and used in the next step without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(C1C=CC(CN2C(CCl)=CN=C2)=CC=1)#N.Cl.[C:47]([C:49]1[CH:63]=[CH:62][C:52]([CH2:53][N:54]2[C:58](CCl)=[CH:57][N:56]=[C:55]2[CH3:61])=[CH:51][CH:50]=1)#[N:48]>>[C:47]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]2[C:58]([CH2:6][N:8]3[CH2:9][CH2:10][C:11]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=4)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:57][N:56]=[C:55]2[CH3:61])=[CH:62][CH:63]=1)#[N:48]
Reactant: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Reactant: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: N#Cc1ccc(Cn2cncc2CCl)cc1
Product: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(Cc2cnc(C)n2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using the protocol described in Example 61, Step B-C substituting methyl N-tert-butoxycarbonyl-4-(3-methylbenzyl)piperidine-4-carboxylate with ethyl N-tert-butoxycarbonyl-4-(3-nitrobenzyl)piperidine-4-carboxylate in Step B, and 1-(4-cyano-benzyl)-5-chloromethylimidazole hydrochloride salt with 1-(4-cyano-benzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt (Example 53, Step B) in Step C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[C:44](=[O:45])[CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 3.35 mmol) in CH2Cl2 (25 mL), phenylacetyl chloride (0.53 mL, 4.02 mmol) and triethylamine (0.56 mL, 4.02 mmol) are added under N2 atmosphere at 0° C. The mixture is stirred 30 min at 0° C., then allowed to reach RT and further stirred for 1 h. The reaction mixture is diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 20:80 to 0:100) to give the title compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.4. MS (LC-MS): 526 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.71 min.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[C:16](=[O:22])[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].C1OCCOC1.O>[CH:23]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]3[C:16](=[O:22])[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:3]=2)[CH2:25][CH2:24]1
Reactant: Cn1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)c1=O
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)c1=O
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a 50 mL pear shaped flask was added 4-dioxane/water (3.2 mL/0.6 mL). The flask was cooled in an ice/water bath before applying vacuum for 20 minutes. 3-((3-Bromo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.55 g, 1.52 mmol), cyclopropylboronic acid (0.33 g, 3.79 mmol), sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.047 g, 0.091 mmol), palladium acetate (0.01 g, 0.4 mmol), and potassium carbonate (0.84 g, 6.07 mmol) were combined in a 25 mL round bottom flask and placed under vacuum. The degassed solvent mixture was added to the solid reagents and the flask was affixed with a condenser. The apparatus was evacuated and back filled with argon 5 times before heating at reflux under argon for 5 hours. The mixture was cooled to ambient temperature and filtered through a pad of Celite®. The filter cake was washed with ethyl acetate and water. The filtrate phases were separated and the aqueous phase was extracted with ethyl acetate 3 times. The combined organic extracts were washed with saturated sodium bicarbonate 3 times. The organic phase was concentrated under vacuum and dried under high vacuum to give 3-((-cyclopropyl-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridine-2(1H)-one as a beige solid (413 mg).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][C:27]([NH:32]C(=O)OC(C)(C)C)([CH2:30][CH3:31])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.Cl>ClCCl>[NH2:32][C:27]1([CH2:30][CH3:31])[CH2:28][CH2:29][CH:24]([O:23][C:14]2[C:13]3[C:12]4[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:22][CH2:21][C:20]=4[S:19][C:18]=3[N:17]=[CH:16][N:15]=2)[CH2:25][CH2:26]1
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC1(N)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
Into a 25-mL round-bottom flask contained a solution of tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-ethylcyclohexyl)carbamate (240 mg, 0.42 mmol, 1.00 equiv) in dichloromethane (10 mL) was added hydrochloric acid (5 M, 1 mL) and the resulting solution was stirred for 5 hr at RT. The reaction was then quenched saturated aqueous sodium bicarbonate, extracted with 3×40 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 120 mg (80%) of 2-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol as a yellow oil. MS: 362 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[CH:6]([C:16]3[C:17]([S:23][CH3:24])=[N:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[CH:30][N:29]=1>>[Cl:27][C:28]1[N:29]=[CH:30][N:31]=[C:32]([N:20]2[CH:21]=[C:16]([CH:6]3[C:7]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=4[CH:9]=[CH:10][C:4]4[CH:3]=[C:2]([CH3:1])[CH:26]=[CH:25][C:5]3=4)[C:17]([S:23][CH3:24])=[N:18][C:19]2=[O:22])[CH:33]=1
Reactant: CSc1nc(=O)[nH]cc1C1c2ccc(C)cc2C=Cc2cc(C)ccc21
Reactant: Clc1cc(Cl)ncn1
Product: CSc1nc(=O)n(-c2cc(Cl)ncn2)cc1C1c2ccc(C)cc2C=Cc2cc(C)ccc21

Procedure:
The subtitle compound was prepared from the product of step (ii) (0.33 g) and 4,6-dichloropyrimidine (0.149 g) by the method of example 16 step (i). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.23 g. 1H NMR: δ (DMSO) 8.98(d,1H), 8.24(d,1H), 7.61(d,1H), 7.53(d,2H), 7.24(d,2H), 7.23(s,2H), 6.95(s,2H), 5.41(s,1H), 2.42(s,3H), 2.30(s,6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.Cl.[N:15]([O-])=[O:16].[Na+].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Product: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A suspension of 6-amino-1-butyl-1H-pyrimidine-2,4-dione (3.0 g, 16.4 mmol) in a 1N aqueous hydrochloric acid solution (33 mL) at 25° C. was treated with sodium nitrite (1.47 g, 21.32 mmol) in portions. The pH was adjusted to pH=5 by the addition of ammonium hydroxide (22 mL). The reaction was stirred at 25° C. for 10 min. At this time, the resulting solid was collected by filtration, washed with a pH=5 aqueous buffer, and then dried in vacuo to afford 6-amino-1-butyl-5-nitroso-1H-pyrimidine-2,4-dione (2.89 g, 83%) as a purple solid: LR-MS for C8H12N4O3 (M+H)+ at m/z=213.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH2:11][C@H:10]1[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:11][C@H:10]([OH:9])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[C:4](=[O:8])[CH:3]=1
Reactant: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Reactant: O=c1cc(Br)cc[nH]1
Solvent: CCO
Product: O=c1cc(Br)ccn1C[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 22.8 %

Procedure:
To a solution of 4-bromopyridin-2(1H)-one (1 g, 5.747 mmol) in EtOH (3 mL) was added (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (1.087 g, 5.747 mmol). The mixture was heated under microwave conditions at 120° C. for 0.5 h and concentrated. The crude product was purified by column chromatography eluting with DCM/MeOH (10:1). (475 mg, yield 22.8%) MS (ESI+) e/z: 363.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:24])=[CH:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1.[CH3:31][C:32](OC(C)=O)=[O:33]>O1CCOCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:24])=[CH:3][CH2:4][N:5]([C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:32](=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)=CCNc1cc(OCc2ccccc2)c2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)N(CC=C(F)F)c1cc(OCc2ccccc2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.9 %

Procedure:
A solution of 210 (149 mg, 0.46 mmol) in dioxane (5 mL) under Ar was treated with DMAP (50 mg, 0.40 mmol), pyridine (0.37 mL, 4.6 mmol) and Ac2O (0.2 mL, 2.3 mmol) and stirred at 25° C. for 19 h. The reaction solution was quenched by the addition of 10% aqueous HCl (10 mL) and EtoAc (10 mL). The aqueous layer was removed and extracted with EtOAc (3×5 mL). The organic solutions were combined, washed with saturated aqueous NaCl (15 mL), dried (MgSO4), and concentrated under reduced pressure. Chromatography (SiO2, 15% EtOAc-hexane) afforded 211 (162 mg, 169 mg theoretical, 96%) as a pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ8.33 (dd, 1H, J=1.6, 8.1 Hz, C8-H), 7.77 (dd, 1H, J=1.7, 7.5 Hz, C5-H), 7.52 (m, 5H, C6H5), 7.38 (m, 2H, C6 and C7-H), 7.20 (d, 1H, J=1.6 Hz, C4-H), 6.57 (d, 1H, J=1.6 Hz, C2-H), 5.25 (s, 2H, CH2Ph), 4.43 (dtd, 1H, J=1.9, 7.9, 24.8 Hz, C2'-H), 4.32 (dd, 1H, J=1.6, 1.6 Hz, C1'-H), 4.30 (m, 1H, C1'-H), 1.82 (s, 3H, CH3CO); 13C NMR (CDCl3, 100 MHz) δ170.0, 160.0, 157.1, 155.1, 139.4, 135.9, 133.8, 128.2, 127.7, 127.2, 127.1, 126.9, 125.7, 124.7, 121.9, 118.6, 105.0, 74.9 (dd, J=75.2, 91.6 Hz), 69.8, 41.8 (d, J=28 Hz), 22.0; 19F NMR (CDCl3, 376 MHz) δ-87.0 (d, J=40.0 Hz), -89.1 (dd, J=24.8, 40.0 Hz); IR (film) vmax 2928, 1745, 1660, 1413 cm-1 ; FABHRMS (NBA-NaI) m/z 368.1740 (M+H+, C22H19F2NO requires 368.1470).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH:18]([CH3:34])[C:19]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[C:27]=2[Cl:31])[CH:22]=1)=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:3].[ClH:31].[Cl:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:9][CH2:10][N:11]([CH:18]([C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[C:27]=3[Cl:31])[CH:22]=2)=[O:20])[CH3:34])[CH2:12][CH2:13]1
Reactant: Clc1cccc(CN2CCNCC2)c1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4cccc(Cl)c4)CC3)ccc2c1Cl
Yield: 124.5 %

Procedure:
A mixture of N-(3-chlorobenzyl)piperazine dihydrochloride (1.35 g, 5 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.96 g, 6 mmol) and K2CO3 (2.42 g, 17.5 mmol) in 40 ml of DMF was treated according to general preparation 2 to give 1.65 g of compound (IV-36), yield 64%. M+ 444.