Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:25])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20](=O)[CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:25])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20](=[N:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=1[O:27][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCC(=O)c1ccc2c(c1)cc(CCO[Si](C)(C)C(C)(C)C)n2C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc(CCO[Si](C)(C)C(C)(C)C)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 1-(2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indol-5-yl)butan-1-one (6.62 g, 18.41 mmol) in DCM (35 mL) was added 2,4-dimethoxybenzylamine (3.20 mL, 21.30 mmol) and NEt3 (7.0 mL, 50.22 mmol). Mixture was cooled to 0° C. before TiCl4 solution (1M DCM, 12.0 mL, 12.0 mmol) was added dropwise via syringe pump over 30 min. Reaction was allowed to warm to room temperature and stirred overnight. Mixture was diluted with DCM (100 mL) and then quenched with NaHCO3 (aqueous saturated, ˜30 mL). Upon vigorous shaking organic phase was separated using PTFE phase separator and dried over Na2SO4. Removal of the solvent afforded N-(1-(2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indol-5-yl)butylidene)-1-(2,4-dimethoxyphenyl)methanamine as yellow oil, which was taken directly into next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34](OCC1C=CC=CC=1)=[O:35].CC(C)([O-])C.[K+]>C1COCC1>[CH2:27]([O:26][C:24]([C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:13](=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:23][CH:22]=3)[CH:14]([CH:34]=[O:35])[C:15]=2[CH:16]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)c1ccc2c(c1)Cc1cc(C(=O)OCc3ccccc3)ccc1-2
Reactant: O=COCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CC1c2cc(C(=O)OCc3ccccc3)ccc2-c2ccc(C(=O)OCc3ccccc3)cc21
Reaction time: 3 h

Procedure:
In a dry argon-purged flask, 2,7-fluorenedicarboxylic acid dibenzyl ester (3.0 g, 0.0065 mol) was dissolved in anh. THF (60 mL) at room temperature. Benzyl formate (4.2 mL, 0.035 mol, stored over anhydrous K2CO3) was added followed by addition of potassium tert-butoxide 95% (2.7 g, 0.023 mol). The reaction was stirred for three hours then the reaction was quenched with the addition of water and acidified with HCl to pH 2. The organic solvent was partially evaporated at reduced pressure. The product was twice extracted with ethyl acetate (600 mL then 200 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was washed with hexanes and methanol (1.9 g, 60%). 1H-NMR (d6-DMSO): δ (ppm) 11.9 (s, ˜1H, formyl); 8.8 (s, 1H, Ar); 8.5 (s, 1H, Ar); 8.4 (s, 1H, Ar); 8.2 (m, 2H, Ar); 7.9 (m, 2H, Ar); 7.5-7.4 (m, 10H, Bz); 5.4 (s, 4H, Ar).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[Cl-].[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10]([O-])=[O:11]>C(Cl)Cl>[O:11]=[C:10]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)[CH2:9][C:8]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(=O)[O-]
Reactant: C1CSCCN1
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC(=O)N1CCSCC1
Yield: 97.1 %

Procedure:
20.6 g of thiomorpholine were added dropwise to a solution of 13.6 g of methyl malonate monochloride in 100 ml of methylene chloride. After stirring the mixture was diluted with 200 ml of methylene chloride, washed with water in a separating funnel, then dried, filtered and evaporated. The residue was purified by chromatography on silica gel with methylene chloride and then methylene chloride/acetone (1:1). There were obtained 17.6 g of methyl tetrahydro-b-oxo-4H-1,4-thiazine-4-propionate.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:4][CH:3]1[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.Cl[C:15](OC(Cl)(Cl)Cl)=[O:16].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:32][NH:31][N:30]=2)=[CH:25][CH:24]=1>O1CCOCC1.ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:32][N:31]([C:15]([NH:10][C:9]3[CH:11]=[CH:12][C:6]([O:5][CH:3]4[CH2:4][C:2]4([F:13])[F:1])=[CH:7][CH:8]=3)=[O:16])[N:30]=2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(C2=NNCC2c2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OC2CC2(F)F)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC2CC2(F)F)cc1)N1CC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)=N1
Temperature: 100 °C

Procedure:
4-(2,2-Difluorocyclopropyloxy)aniline was dissolved in dioxane (10 ml) and treated with tricloromethyl chloroformate (0.6 ml). The mixture was heated at 100° C. for 3 hours whilst excluding moisture. The mixture was then cooled to room temperature and 3,4-bis-(4-chlorophenyl)-4,5-dihydropyrazole (2.64 g; 9 mmol), dissolved in dichloromethane (30 ml), was added with stirring. After 3 hours the reaction mixture was concentrated and the residue chromatographed on silica gel.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cc(N)ncn2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
After suspending 6-(4-nitrophenoxy)pyrimidin-4-ylamine (306 mg, 1.32 mmol), iron powder (369 mg, 6.60 mmol) and ammonium chloride (706 mg, 13.2 mmol) in an ethanol (20 ml)-water (5 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was concentrated to obtain the title compound (266 mg, 1.32 mmol, 100%) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O>>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([NH2:1])=[N:3]2)=[C:8]([Cl:26])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc(N)[nH]c2c(=O)[nH]1
Solvent: CCN(CC)c1ccccc1
Product: Nc1nc(Cl)c2[nH]c(N)nc2n1

Procedure:
A suspension of 8-aminoguanine (Fischer, Z. Physiol. Chem., 60, 69 (1909); Beaman et al., in Zorbach and Tipson, Synthetic Procedures in Nucleic Acid Chemistry, Vol. 1, pp 41-43, John Wiley & Sons, New York, 1968) (3.0 g, 18.1 mmol) in phosphorus oxychloride (90 mL) and N,N-diethylaniline (3 mL) was refluxed for 30 min and the excess phosphorus oxychloride was evaporated under reduced pressure. Ice (20 g) was added slowly to the resulting solution and the pH was adjusted to 6 with a concentrated aqueous sodium hydroxide solution. A yellow solid formed and was collected by filtration, washed with water, and dried to give a green solid. Crystallization from water with charcoal treatment produced 2,8-diamino-6-chloropurine as a white solid: yield, 2.11 g (63%); mp >275° C. dec.; 1H NMR δ6.09 (s, 2H, NH2, exchange with D2O), 6.71 (s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C5H5N635Cl 184.0264, found 184.0266; calcd. m/z C5H5N637Cl 186.0235, found 186.0237.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]2[CH:33]=[CH:32][C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2.C(OC)(C)(C)C>C(O)(C)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]2[CH:33]=[CH:32][C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[CH2:19]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.98 g, 15.3 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-N-isopropylbenzamide (4.00 g, 15.7 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.17 g, 7.68 mmol) in isopropyl alcohol (10 mL) was heated at 70° C. for 1 h. The mixture was cooled down to 35° C. To the suspension was added 30 ml of methyl tert-butyl ether (MTBE), and stirred at room temperature for 1 h. The precipitates formed was collected by filtration, washed with MTBE, and dried under reduced pressure to afford the desired product (6.2 g 89.8%). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 4.40 (d, J=8.6 Hz, 2H), 4.20 (d, J=8.6 Hz, 2H), 4.05 (m, 1H), 3.65 (s, 2H), 1.24 (s, 12H), 1.12 (d, J=6.6 Hz, 6H) ppm. LCMS cacld. for C24H33BN5O3 (M+1)+: m/z=450.3. Found: 450.3.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=O)O[C:8](=O)[C:4]=2[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14].[ClH:17].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:17].[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:8]2
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CC(C)N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)N1Cc2ccc(Br)cc2C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
5-bromo-2-benzofuran-1,3-dione (1 wt) was suspended in toluene (5 vol) with stirring under nitrogen. Isopropylamine (1.1 eq, 0.416 vol) was then added dropwise over 10-30 mins at such a rate as to maintain the temperature between 15-25° C. (exothermic addition). The batch was stirred for a further 30 mins at 15-25° C. once the addition was complete, before heating to reflux under Dean-Stark conditions. The batch was held at reflux for 5-8 hrs until residual 5-bromo-2-benzofuran-1,3-dione by HPLC is <1% a/a uncorrected, then the batch was concentrated atmospherically to ca 2.5 vols2. Added toluene (3 vols) and reconcentrated atmospherically to ca 2.5 vols. Batch then cooled to 55-60° C., diluted with THF (1.5 vols), and then further cooled to 15-25° C. This was added to a solution of borane-THF complex (1.0M, 4 eq, 14.1 vol) and the resultant solution was stirred at 20-30° C. for ca 30 mins. The batch was then heated to 48-52° C., and held thus for 16-24 hrs until complete by HPLC, before cooling back to 15-25° C. The reaction was quenched inversely into aqueous hydrochloric acid (2N, 9 vol) over at least 30 mins maintaining an internal temp of 15-30° C. (initially effervescent, evolves hydrogen). Once the addition was complete, the batch was heated to 60-63° C., and held thus for 1-1.5 hrs before cooling to 15-25° C. Ethyl acetate (6 vols) was added and the resultant biphase was shaken, settled and separated1. Organics back-extracted with 2N HCl (3 vols) before being discarded. The combined aqueous liquors were then neutralized to pH>12 with 40% w/v aq NaOH (approx 3.9 vols). Overlain with ethyl acetate (6 vols) then the resultant biphase was shaken, settled and separated. Aqueous back extracted with ethyl acetate (3 vols) before being discarded. The organics were combined and washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols. Ethyl acetate (8 vols) was added and the batch was reconcentrated in vacuo to ca 4 vols. Ethyl acetate (9 vols) was added and the batch was adjusted to 0±3° C. 4M HCl in dioxane (0.89 eq, 0.98 vol) was then added slowly maintaining the batch temp within the range 0±3° C. The batch was then aged within this range for 30 min before product was collected by vacuum filtration. Washed with chilled ethyl acetate (<5° C., 2×2 vols) and dried o/n in vacuo at 30° C. to constant weight.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[CH:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[C:6]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH3:30])=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:18]1([S:15]([CH:14]=[CH:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[NH:4][CH:5]=[C:6]3[CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH3:30])(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)n1cc(C[C@H]2CCCN2C)c2cc(C=CS(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A suspension of (R)-1-acetyl-5-(benzenesulfonylethenyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole (220.8 g) in methanol (2.21 L) was treated with potassium carbonate (72.23 g) and stirred at ambient temperature. After about one hour active carbon (22.1 g) was added to the solution then water (660 mL) added slowly. The mixture was filtered and the filtrate heated to reflux and water (660 mL) added dropwise. The mixture was allowed to cool and crystallize, then further water was added slowly (3.31 l). The resulting solid was filtered, washed with 1:2 methanol:water mixture (2×200 mL) then dried in vacuo to give the title compound (149 g): mp, 84°-87° C. IR (KBr) 1600, 1450, 1290, 1145, 1085 cm-1 : 1H NMR (CDCl3) 8.4 (b, 1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.6-7.5 (m, 3H), 7.3 (s, 2H), 7.05 (b, 1H), 6.75 (d, 1H), 3.15 (m, 2H), 2.6 (m, 1H), 2.45 (s, 3H), 2.4 (s, 1H), 2.2 (m, 1H), 2.0-0.5 (m, 4H); LRMS (TSP), m/z 381, 165, 133, 119.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]4[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=4[S:20][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1Br)(=O)C.[CH3:28][N:29]([CH3:58])[CH2:30][CH2:31][N:32]([CH3:57])[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40]2[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)=[N:37][CH:38]=1>>[CH3:28][N:29]([CH3:58])[CH2:30][CH2:31][N:32]([CH3:57])[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40]2[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:17][CH2:16][C:15]5[C:18]6[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=6[S:20][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:45]=2)=[N:37][CH:38]=1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CN(C)CCN(C)c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Product: CN(C)CCN(C)c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(sc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 7.8 %

Procedure:
Following Example 270, reaction of 212a (550 mg, 1.20 mmol) and 270d (428 mg, 1.00 mmol) afforded a 8% yield (49 mg) of 286 as an off-white solid: mp 122-123° C.; 1H NMR (500 MHz, DMSO-d6) d 8.45 (d, 1H, J=2.0 Hz), 8.20 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 7.31 (m, 2H), 7.17 (m, 3H), 4.83 (t, 1H, J=4.6 Hz), 4.32 (d, 2H, J=4.3 Hz), 4.06 (m, 1H), 3.87 (m, 1H), 3.58 (s, 3H), 2.96 (m, 1H), 2.86 (m, 1H), 2.83 (s, 3H), 2.78 (m, 2H), 2.54 (m, 1H), 2.32 (t, 2H, J=7.0 Hz), 2.14 (s, 6H), 1.80 (m, 4H); MS (ESI+) m/z 631.3 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([F:30])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:21]([CH3:23])[N:22]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33]>C(NC(C)C)(C)C.CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:30][C:3]1[C:2]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])=[CH:29][C:6]2[C:7]3[N:8]([C:12]([C:18]4[N:19]([CH2:24][C:25]([F:27])([F:28])[F:26])[N:20]=[C:21]([CH3:23])[N:22]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: Cc1nc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)n(CC(F)(F)F)n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)n(CC(F)(F)F)n1
Temperature: 85 °C

Procedure:
The title compound was prepared similarly according to Procedure E. To a solution of 10-bromo-9-fluoro-3-[5-methyl-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (200 mg, 0.41 mmol), PdCl2(PPh3)2 (0.05 equiv., 14.5 mg, 0.02 mmol) and copper (I) iodide (0.05 equiv., 4.0 mg, 0.02 mmol) in diisopropylamine (1.1 mL, 2.6 mL/mmol) and DMF (0.53 mL, 1.3 mL/mmol) was added 2-methyl-3-butyn-2-ol (2.0 equiv., 0.08 mL, 0.82 mmol). The reaction was heated to 85° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with methylene chloride and filtered over celite. The crude was purified by reverse-phase HPLC to afford 73 mg (36.3% yield) of a fluffy white solid. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=8.5 Hz, 1H), 7.99 (br s, 1H), 7.48 (br s, 1H), 7.05 (d, J=10.5 Hz, 1H), 5.53 (s, 1H), 5.12-4.96 (m, 2H), 4.56-4.47 (m, 2H), 4.30-3.98 (m, 2H), 2.37 (s, 3H), 1.50 (s, 6H). M+H=493.2.
Reaction SMILES: O=[C:2]([CH3:6])[C:3](=[S:5])[NH2:4].[Br:7][C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]2=[NH:23]>C(#N)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]12[NH:4][C:3](=[S:5])[C:2]([CH3:6])=[N:23]1
Reactant: CC(=O)C(N)=S
Reactant: N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Solvent: CC#N
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)NC1=S

Procedure:
2-Oxopropanethioamide (Intermediate 2, 289 mg, 2.80 mmol) and 6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-imine (Example 45 Step 2, 331.4 mg, 1.12 mmol) were dissolved in acetonitrile (3 mL) and heated using MW for 20 min to 120° C. The solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in heptane but co-eluted with byproducts. The not completely pure product was used as a mixture in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:24]([O:23][C:21]([CH:20]1[CH2:26][CH2:27][N:17]([CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]=2)[CH2:18][CH2:19]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3-formyl-phenyl)-carbamic acid tert-butyl ester (Schadendorf T et al., Tetrahedron Letters (2007), 48(51), 9044-9047), (1 g, 4.52 mmol), ethyl isonipecotate (800 mg, 5.09 mmol) and TEA (0.7 mL, 5 mmol) in MeOH (50 mL) is treated with acetic acid (1.03 mL, 18 mmol) and stirred at RT for 2 h. Sodium cyanoborohydride (398 mg, 6.33 mmol) is added at once and the reaction mixture is stirred for 18 h at RT. Water (5 mL) is added to the mixture and the solvents are evaporated. The residue is partitioned between diethyl ether (50 mL) and aqueous 0.1N HCl (50 mL). The aqueous phase is separated, washed twice with diethyl ether (25 mL) and basified with 1N NaOH solution (10 mL). The aqueous phase is extracted three times with DCM (3×50 mL). The combined organic phases are dried over MgSO4 and evaporated. The title compound is obtained as a thick oil; LC-MS A: tR=0.71 min; [M+H]+=363.48.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([CH2:8][OH:9])[CH2:4][CH:3]1[N+:10]1[CH:15]=[CH:14][CH:13]=[C:12](C(OC)=O)[CH:11]=1.[CH3:20][S:21]([O-:24])(=[O:23])=[O:22].[NH3:25].[CH3:26][OH:27]>>[C:26]([C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH:3]1[CH2:4][CH:5]([CH2:8][OH:9])[CH:6]([OH:7])[CH:2]1[OH:1])(=[O:27])[NH2:25].[CH3:20][S:21]([O-:24])(=[O:23])=[O:22]
Reactant: CO
Reactant: N
Reactant: COC(=O)c1ccc[n+](C2CC(CO)C(O)C2O)c1
Agent: CS(=O)(=O)[O-]
Product: NC(=O)c1cccc[n+]1C1CC(CO)C(O)C1O
Reaction time: 2.5 h

Procedure:
Crude 1-(2,3-Dihydroxy-4-hydroxymethyl-cyclopentyl)-3-methoxycarbonyl-pyridinium-methansulfonate (118.3 g, 173.7 mmol) was dissolved in 100.0 ml methanol. After the addition of methanolic ammonia (7M, 350.0 ml, 2.45 mol) the reaction mixture was stirred for 2.5 hrs. After removing the solvent under reduced pressure, a red-brown oil was obtained that was further dried for 3 hrs. (40° C., 10 mbar). This crude product may be pre-purified with activated charcoal and may be used directly for the chemical synthesis of cNAD (WO2007/012494) or in the enzymatic synthesis of cNAD as described herein.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([NH:19][C:20](=[O:37])[O:21][CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:12]2>C(OCC)(=O)C>[Cl-:1].[F:36][C:32]1[CH:31]=[C:30]([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[O:21][C:20]([NH:19][C@@H:13]2[CH:14]3[CH2:17][CH2:18][N+:11]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:16][CH2:15]3)[CH2:12]2)=[O:37])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
2-Chloro-1-phenylethanone (20.8 mg, 0.13 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (50 mg, 0.13 mmol, prepared as in example 1) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight, then the solvent was evaporated under vacuum. The residue was treated with Et2O (4 ml) and sonicated to obtain a solid, which was collected by suction filtration and purified by flash chromatography (DCM/MeOH=95/5), to obtain (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (37.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][C:7](=[O:14])[CH2:6]1)=[O:4].[CH2:15](O)[CH2:16][OH:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:15]1[CH2:16][O:17][CH:6]2[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH:7]2[O:14]1
Reactant: COC(=O)C1CC(=O)CC1C(=O)OC
Reactant: OCCO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1CC2OCCOC2C1C(=O)OC
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
In 250 ml of dichloromethane were dissolved 124 g of 3,4-dimethoxycarbonylcyclopentanone and 155 g of ethylene glycol and to the solution was added dropwise 94 g of boron trifluoride ethyl etherate at 0° - 5°C. After completion of the addition, the reaction mixture was stirred for 2 hours at 10° - 16°C and next for 1.5 hours at 16° - 23°C. After completion of the reaction, the reaction mixture was added dropwise to 1.5l of a saturated aqueous sodium bicarbonate containing pieces of ice in order to decompose the excess of the boron trifluoride etherate. The mixture was extracted three times with 1 l of ether. The extract was washed with a saturated aqueous sodium chloride and a saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give 135.7 g of the desired product as colorless oil.