Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1>C(Cl)Cl>[O:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH:63]1[O:62][NH:61][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:21]=3[CH2:20]2)=[N:27][CH:26]=1)=[O:29]
Reactant: O=C(O)c1cnc(N2CCc3c(n(CCN4CCCCC4)c4ccccc34)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(CCN4CCCCC4)c4ccccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of the acid 2-[9-(2-piperidin-1-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylic acid (200 mg, 0.49 mmol) in DCM (20 mL) was added EDCI (140 mg, 0.73 mmol), HOBT (99 mg, 0.73 mmol), DIEA (183 mg, 1.46 mmol) and NH2OTHP (57 mg, 0.48 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-(2-piperidin-1-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (80 mg). 1H NMR (200 MHz, CDCl3) ppm: 8.75 (s, 2H), 7.50 (d, 1H, J=7.0 Hz), 7.30 (m, 1H), 7.16 (m, 2H), 5.13 (s, 2H), 5.04 (s, 1H), 4.24 (m, 4H), 4.00 (m, 1H), 2.91 (m, 2H), 2.70 (m, 2H), 2.49 (m, 4H), 1.85-1.45 (m, 11H); m/e=504 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[B:34]1(B2OCC(C)(C)CO2)[O:39]CC(C)(C)C[O:35]1.CC([O-])=O.[K+].O1CCOCC1>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:33])[CH:9]([CH3:32])[C:10]([NH:12][C:13]1[N:14]=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:16]([B:34]([OH:39])[OH:35])=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C(=O)Nc1ccc(Br)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]-N-methylcarbamate C1a (51 g, 90 mmol), bis(neopentyl glycolato)diboron (40.5 g, 179 mmol), KOAc (26.4 g, 269 mmol), 1,1′-Bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (3.3 g, 4.5 mmol) and dioxane (400 ml) is stirred under argon atmosphere for 17 h at 50° C. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 21.9 g (48%). HPLC-MS: M+H=504; tR=2.17 min (*Method—4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[CH:9]=2)=[CH:4][N:3]=1.ClC1N=C(N2CCOCC2)N=C(C2C=NC(N)=NC=2)C=1.NC1C=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=NC=1.Cl>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[CH:23][CH:22]=3)[CH:9]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(-c4cnc(N)nc4)nc(N4CCOCC4)n3)cn2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Agent: Cl
Agent: Nc1ncc(-c2cc(Cl)nc(N3CCOCC3)n2)cn1
Solvent: C1COCCO1
Product: Nc1ncc(-c2cc(Nc3ccc(N4CCNCC4)nc3)nc(N3CCOCC3)n2)cn1
Reaction time: 1 h

Procedure:
To tert-butyl 4-(5-(6-(2-aminopyrimidin-5-yl)-2-morpholinopyrimidin-4-ylamino)pyridin-2-yl)piperazine-1-carboxylate (prepared as described in Example 1 from 5-(6-chloro-2-morpholinopyrimidin-4-yl)pyrimidin-2-amine and commercially available tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate, 30 mg, 0.06 mmol) were added 5 mL of 4N HCl in dioxane. After stirring for one hour, the solution was concentrated in vacuo. The residue was dissolved in a 3:1 acetonitrile and water and lyophilized to afford the desired product LC/MS (m/z): 435.2 (MH+), Rt 1.52 minutes.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:33](=[O:34])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19]Cl)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)COc4ccccc4)C(=O)N23)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C1CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 65 %

Procedure:
To a solution of 48 ml of SmI2 in THF (0.1M), a solution of 1.1 g of p-methoxybenzyl 7β-phenoxyacetylamino-3chloromethyl -3-cephem-4carboxylate in 100 ml of dry THF, was dropwise added at -20° C. The resulting mixture was allowed to warm to room temperature in 0.5 hours. Water was added, and the mixture stirred for further 0.2 hours at room temperature. After the usual work-up and column chromatography, the title product was isolated in 65% yield.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][CH:6]([O:8][C@H:9]([CH3:17])[C:10](OCC(C)C)=[O:11])[CH3:7])[CH3:4].CO.O>ClC1C=CC=CC=1>[CH2:3]([O:5][CH:6]([O:8][C@H:9]([CH3:17])[CH2:10][OH:11])[CH3:7])[CH3:4]
Reactant: CCOC(C)O[C@H](C)C(=O)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: CO
Product: CCOC(C)O[C@H](C)CO
Yield: 78.3 %

Procedure:
1.85 g of sodium borohydride was suspended at room temperature in a solution of 7.52 g of the isobutyl (R)-(+)-2-(1-ethoxyethoxy)propionate (obtained in Reference Example 3) dissolved in 30 ml of chlorobenzene. Thereto was dropwise added slowly 7.3 ml of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. to give rise to a reaction. After the reaction, thereto was added 60 ml of water, followed by extraction with 120 ml of ethyl acetate. The water layer was subjected to extraction with 60 ml of ethyl acetate. The two organic layers were combined and washed with a saturated aqueous sodium chloride solution. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 4.0 g (yield: 90.8%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]([CH3:16])[C:7](=[O:9])[C:6]([CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=1
Reactant: CI
Reactant: COc1nc(C)c(CCO)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(C)c(CCO)c(=O)n1C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methoxy-5-(2-hydroxyethyl)-6-methyl-3H-pyrimidin-4-one (2.6 g, 0.014 mol) in DMF (25 ml) was added one equivalent of sodium hydride (55%, 0.6 g). After stirring for 0.5 hr. methyl iodide (0.81 ml, 0.014 mol) was added and the mixture was heated at 50° C. for five hours. After cooling, most of the DMF was removed in vaccuum. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated. Yield 2.0 g (71%) of a yellow oil.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][N:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C(NC1N=C2C(N=CN2[CH:25]2[CH:29]([O:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH:27]([CH:39]=[CH:40][P:41]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:42])[O:26]2)=C(OC(=O)N(C2C=CC=CC=2)C2C=CC=CC=2)N=1)(=O)C.C(OP(C=CC1CC(C(=O)C2C=CC=CC=2)C(C(=O)C2C=CC=CC=2)O1)(=O)OCC)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CC#N>[NH2:3][C:2]1[NH:1][C:10](=[O:11])[C:9]2[N:8]=[N:7][N:6]([CH:25]3[CH:29]([O:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH:27]([CH:39]=[CH:40][P:41]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:42])[O:26]3)[C:5]=2[N:4]=1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(C)=O)nc32)O1)OCC
Reactant: Nc1nc2nn[nH]c2c(=O)[nH]1
Agent: CCOP(=O)(C=CC1CC(C(=O)c2ccccc2)C(C(=O)c2ccccc2)O1)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2nnc3c(=O)[nH]c(N)nc32)O1)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
8-Azaguanine was persilylated first using the procedure described for the preparation of compound 9.9. Compound 9.8 (490 mg, 1.03 mmol) was dissolved in 20 mL anhydrous CH3CN, and treated with 10 mL CH3CN solution of persilylated 8-azaguanine base (392.9 mg, 1.03 mmol), followed by addition of SnCl4 (1M solution in CH2Cl2) (3 mL, 3 mmol). The mixture was stirred at r.t. for 24 h, cooled with ice-water and NaHCO3, filtered, and concentrated down under reduced pressure. The residue was subjected to a silica gel column eluting with 10% EtOH in EtOAc to give compound 10.1 (430 mg, 83% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[F:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(F)c(F)c1C)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(F)c(F)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Yield: 110.9 %

Procedure:
3,4-Difluoro-2-methylbenzyl-2,2-dimethoxyethylamine (23, 37.8 g) was dissolved in dichloromethane (100 mL). Pyridine (42 mL) was added. At 0° C. a solution of p-toluenesulphonyl chloride (36.8 g, 193 mmol) in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring continued until the conversion was complete. For workup, the reaction mixture was diluted with dichloromethane (100 mL) and extracted twice with 1.5M hydrochloric acid, twice with sodium bicarbonate solution and once with brine. The organic layer was dried over magnesium sulphate, evaporated to dryness to give crude product as an orange oil (68.3 g). This was used without further purification.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[O:14][N:13]=[C:12]([CH:15]([OH:17])[CH3:16])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]>C(C#N)(C)=O.O=[Mn]=O>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[O:14][N:13]=[C:12]([C:15](=[O:17])[CH3:16])[CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)on1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-isoxazol-3-yl]-ethanol (1.79 g, 6.95 mmol) in AcCN (70.0 mL) was treated at rt with MnO2 (3.36 g, 34.77 mmol) and the reaction mixture was stirred for 72 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 2: tR=1.13 min.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH:44]1[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([N:44]3[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]3)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: OC1CCNC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N=C(NCC(=O)N2CCC(O)C2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and pyrrolidin-3-ol (0.23 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (90 mg).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[NH2-].[Na+].[C:15](#[N:17])[CH3:16]>>[CH3:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([CH2:16][C:15]#[N:17])=[O:12]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1OC
Agent: [NH2-]
Agent: [Na+]
Product: COc1ccccc1C(=O)CC#N
Yield: 84 %

Procedure:
In agreement with this data the condensation of 2-methoxybenzoic acid methyl ester with acetonitrile using sodamide/liquid ammonia gives 2-methoxybenzoylacetonitrile in 84% yield, in contrast this same reaction using sodium hydride in benzene only leads to a 27.4% reaction yield. (Kawase, Bull, Chem. Soc. Japan, Vol. 35 (1962), pages 1869-1871.)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[NH2:14]>CN1C(=O)N(C)CCC1>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Reactant: CSc1ccc(C(=O)CBr)cc1
Solvent: CN1CCCN(C)C1=O
Product: CSc1ccc(-c2coc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 145 °C
Yield: 25.1 %

Procedure:
2-Bromo-1-[4-(methylsulfanyl)phenyl]ethanone (5 g, 19.15 mmol) and tert-butyl 4-carbamoylpiperidine-1-carboxylate (4.37 g, 19.15 mmol) were dissolved in DMPU (40.8 mL) and heated to 145° C. for 15 min. The resulting solution was then cooled to room temperature, partitioned between aqueous LiCl and ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo. The resulting crude oil was purified using silica gel chromatography (300 g, using 20-80% ethyl acetate in hexane gradient) to yield 1.8 g of the desired product as a yellow oil. LCMS (M+1)=375.40
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.[F-].[Cs+].CN(C=O)C>O.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]3=[O:17])=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OC)cc3)ccn2c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 52.6 %

Procedure:
An oven-dried 50 ml round-bottom flask equipped with reflux condenser was purged with argon, followed by addition of ethyl 8-chloro-4-oxo-4H-quinolizine-3-carboxylate (2) (500 mg, 2 mmol), 4-methoxyphenylboronic acid (372 mg, 2.4 mmol), CsF (600 mg, 3.9 mmol), PdCl2[P(c-Hex)3]2 (80 mg, 0.1 mmol) and 6 ml DMF. The reaction mixture was stirred at 110° C. for 12 h and cooled to room temperature. Completion of the reaction was indicated by thin layer chromatography (ethyl acetate). The reaction mixture was poured into 100 ml water and extracted three times with 100 ml chloroform. The combined organic layers were washed three times with 50 ml water. The organic solvent was evaporated and the crude product was further purified by column chromatography (5% MeOH in ethyl acetate) to give a bright yellow solid (340 mg, 50% yield). M.p. 205-209° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz, 3H), 3.90 (s, 3H), 4.42 (q, J=7 H, 2H), 6.65 (d, J=8 Hz, 1H), 7.05 (d, J=9 Hz, 2H), 7.43 (dd, J=2 Hz, J=7 Hz, 1H), 7.58-7.80 (m, 3H), 8.37 (d, J=8 Hz, 1H), 9.41 (d, J=7 Hz, 1H). MS: m/z 323.1159; required for C19H17NO4: 323.1157.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2=[O:9].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[K+]>CC(O)C.O.CCOCC>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:3]2[CH:4]3[CH2:7][CH2:8][CH:1]([CH:6]=[CH:5]3)[C:2]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CC2C=CC1CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C1C(=Cc2ccc(F)cc2)C2C=CC1CC2
Temperature: 25 °C

Procedure:
A solution of bicyclo[2.2.2]oct-5-en-2-one (J. Org. Chem. 33, 2211 (1968)) (3.34 g, 27.4 mmoles), 4-fluorobenzaldehyde (3.08 ml, 28.7 mmoles) and KOH (2 pellets) in 10 ml of 2-propanol was heated at 60° C. for 1.5 hours, cooled to room temperature and diluted with H2O and ether. The organic layer was washed with H2O, 2% aqueous HCl, saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was recrystallized with hexanes. mp 85°-86° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K].[C:25]1([CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: NS(=O)(=O)CCc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccc1
Yield: 78.1 %

Procedure:
A solution of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2 g) and 2-phenyl-ethanesulfonic acid amide potassium salt (2.82 g, Referential Example 1e) in DMF (50 ml) was stirred at rt for 16 h. Bulk of the solvent was evaporated before it was diluted with diethyl ether (50 ml). The mixture was acidified with 10% aq. citric acid. The precipitate that formed was collected, washed with diethyl ether (100 ml) and dried to give 2-phenyl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (2.23 g) as a beige powder. LC-MS: tR=4.93 min, [M+1]+=497.22, [M−1]−=494.96.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[N:56]1([C:62](Cl)=[O:63])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:55])=[O:4])=[O:24])[N:26]([C:62]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[O:63])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N3CCOCC3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (21 mg) was reacted with morpholine-4-carbonyl chloride according to General Procedure H. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (11 mg). LCMS (m/z): 852.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml) and triethylamine (190 ul, 1.35 mmol), was added 4-chlorobenzene-1-sulfonyl chloride (114 mg, 0.54 mmol). The reaction was stirred at RT for 3 hours, and then the solvent was evaporated. The crude was taken up with EtOAc and washed with water, brine and then with K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(4-chlorophenylsulfonamido)-2-phenylacetate (62 mg; 32% yield), which was used as such in the next step.
Reaction SMILES: O[CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2.[OH:15]C1C2CC3(C(O)=O)CC(CC1C3)C2>>[OH:15][C:9]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]([C:12]([OH:14])=[O:13])([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1O)C2
Reactant: O=C(O)C12CC3CC(C1)C(O)C(C3)C2
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
2-Hydroxyadamantane-1-carboxylic acid and 4-hydroxy adamantane-1-carboxylic acid: J. Org. Chem., 38, 3447 (1973).