Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([NH:28][C:29]([NH:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCCn1c2c(cc(N)c1=O)CCCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCn1c2c(cc(NC(=O)NCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
3-Amino-1-butyl-5,6,7,8-tetrahydro-1H-quinolin-2-one acetic acid salt (6-001-01) (5 mg, 0.018 mmol) was dissolved in methylene chloride (1 mL), and to the reaction mixture were added benzylisocyanate (2.5 μL, 0.02 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol), and the reaction mixture was stirred at room temperature for 4 h. To the reaction mixture was added diluted hydrochloric acid (0.1 mol/L, 3 mL), and the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (3 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-benzyl-3-(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)urea (6-005) (5.0 mg, 79%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:19](=[O:38])[N:18]2[C:39](OC2C=CC([N+]([O-])=O)=CC=2)=[O:40])=[CH:13][CH:12]=1)#[N:10].O>O1CCCC1>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:19](=[O:38])[N:18]2[C:39]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[O:40])=[CH:15][CH:16]=1)#[N:10]
Reactant: CC(C)(C)CO
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2,2-dimethyl-1-propanol (9 mg, 0.10 mmol) in dry tetrahydrofuran (1 mL) is cooled at −78° C. and treated with sodium hydride (60% in mineral oil, 5 mg, 0.11 mmol). After 20 min, a solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 60 mg, 0.10 mmol) in tetrahydrofuran (1 mL) is added and the mixture is stirred for 5 h at room temperature. Another portion of 2,2-dimethyl-1-propanol (9 mg, 0.10 mmol) is added and the mixture is stirred over night. Another portion of 2,2-dimethyl-1-propanol (18 mg, 0.20 mmol) is added and the mixture is heated at 50° C. for 2 h. Water is added and the mixture is extracted with dichlormethane. The organic layer is concentrated under reduced it) pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane to cyclohexane/ethyl acetate 1:1). Yield: 12 mg; ESI mass spectrum [M+H]+=526; Retention time HPLC: 0.76 min (X012_S01).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].O>CO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([OH:9])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2cc(Cl)ncn2)c1

Procedure:
The reaction of 4,6-dichloropyrimidine with excess 3-hydroxyaniline in MeOH at 800° C. for 24 h followed by dilution with water and acidification gave the crude product which was purified by silica gel column chromatography to obtain 6-chloro N4-(3-hydroxyphenyl)-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.36 (d, 1H, J=1.2 Hz), 7.15 (t, 1H, J=8.4 Hz), 6.93 (dd, 1.2 and 8.1 Hz), 6.74 (d, 1H, J=1.2 Hz), 6.55 (dd, 1.8 and 8.1 Hz); LCMS (m/e): ret. time: 19.75 min.; purity: 99%; MS (m/e): 222 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[F:24][C:10]([CH:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:11]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-L-Proline (4.5 g, 0.02 mmol) and pyridine (8.45 mL, 0.104 mmol) in DCM (20 mL) cooled in an ice bath was added dropwise cyanuric fluoride (5.35 mL, 0.0627 mmol). After the addition the reaction became milky. The solution was stirred at 0° C. for 10 min then warmed to RT and stirred for 4 h. The reaction was quenched with water, and thrice extracted with DCM. The combined organic extracts were washed with brine, dried, and concentrated in vacuo to afford tert-butyl 2-(fluorocarbonyl)pyrrolidine-1-carboxylate. The crude acid fluoride was used in next coupling reaction immediately.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].C[O:13][C:14](=[O:18])C[N+]#[C-].C([N:21]([CH2:24][CH3:25])[CH2:22]C)C.N>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:22]=[N:21][C:24]=2[CH2:25][C:14]([OH:18])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Reactant: [C-]#[N+]CC(=O)OC
Agent: N
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ocnc2CC(=O)O)c1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield by the condensation of 3-cyanobenzoyl chloride, methyl-isocyanoacetate and triethylamine in anhydrous THF following the general method of Suzuki et. al. Syn. Comm. 1972, 2, 237. 1H NMR (CDCl3) δ: 8.42-8.40 (d, 1H), 7.99 (s, 1H), 9.77-7.75 (d, 1H), 7.63 (t, 1H), 3.99 (s, 3H) ppm; Ammonia mass spectrum analysis m/z (rel intensity) 246(M+NH4+, 100), 229(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:12][CH:13]=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=3)=[CH:17][CH:16]=2)[CH2:12][CH:13]=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=CCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(Br)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C=CCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2cccc(C#N)c2)cc1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To an Argon-purged solution of 2-(4-bromophenyl)-pent-4-enoic acid (3,5-dichloro-phenyl)-amide (1.5 g, 3.7 mmol) in toluene/EtOH (2:1 v/v, 30 mL) was added 3-cyanophenylboronic acid (0.99 g, 6.7 mmol, 1.8 eq), Pd(PPh3)4 (160 mg, 0.44 mmol, 12%), and a solution of Na2CO3 (2.12 g, 20 mmol, 5.4 eq) in 10 mL of water. The reaction mixture was heated at 90° C. for 16 h. The mixture was partitioned between EtOAc (50 mL) and 10% NaHCO3 (50 mL) and the organic phase separated. The organic phase was washed with 10% NaHCO3 (30 mL) and saturated brine (30 mL), dried (Na2SO4), and concentrated. Chromatography on silica gel (20% EtOAc/hexanes) gave 2-(3′-cyano-biphenyl-4-yl)-pent-4-enoic acid (3,5-dichloro-phenyl)-amide as a yellow oil (685 mg, 44%). 1H NMR (300 MHz, CD3OD): δ 7.93 (m, 2H), 7.81 (m, 2H), 7.66 (m, 4H), 7.49 (m, 2H), 7.12 (t, 1H), 5.89 (m, 1H), 5.21 (m, 2H), 3.76 (t, 1H), 3.11 (m, 1H), 2.73 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[O:25]1[CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(-c2ccn[nH]2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 18.1, 100 mg, 0.224 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (125 mg, 0.448 mmol), Pd(Ph3P)4 (25.9 mg, 0.022 mmol) and K3PO4 (190 mg, 0.896 mmol) and toluene (1.121 mL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred for 16 h at 110° C. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 10% to 60% EtOAc). The fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was treated with TFA (500 μL, 6.49 mmol) and DCM (1.5 mL) and then stirred at RT for 4.5 h. The RM was diluted with DCM (30 mL) and washed with water, sat. aq. NaHCO3, brine and dried over Na2SO4. The solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column Diol, from 20% to 25% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.07-3.25 (m, 4H) 3.55-3.75 (m, 4H) 6.62-6.82 (m, 1H) 7.36 (d, J=8.53 Hz, 2H) 7.54-7.88 (m, 1H) 7.85-7.92 (m, 2H) 8.20-8.40 (m, 1H) 8.76 (d, J=2.13 Hz, 1H) 10.44 (br. s, 1H) 13.02-13.31 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[CH2:26][CH3:27])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N:34][CH:33]=[CH:32]2.O.[C:55]([OH:59])(=[O:58])[CH:56]=O>>[C:50]([O:49][C:47]([N:39]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C:35]1[C:36]2[C:31](=[CH:30][C:29]([NH:28][CH:56]([C:18]3[CH:19]=[C:20]([CH2:21][CH3:22])[C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[C:16]([CH2:26][CH3:27])[CH:17]=3)[C:55]([OH:59])=[O:58])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1)=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCc1cc(B(O)O)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Solvent: O
Product: CCc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Yield: 75 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 37E (200 mg, 0.55 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 38A (304 mg, 75%) as a yellow oil. MS (ESI) m/z 738.22 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.CN(C(O[N:47]1N=[N:54][C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN(C=O)C>[C:48]([CH2:49][NH:54][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)#[N:47]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Yield: 75.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 50 mg, 0.116 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.102 mL, 0.927 mmol), 2-aminoacetonitrile, HCl (13.94 mg, 0.151 mmol), and HATU (66.1 mg, 0.174 mmol). This was stirred overnight before EtOAc was added. The EtOAc solution was washed with 1N HCl, sat NaHCO3, and brine. The organic layer was then dried with MgSO4 and concentrated to give N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (51 mg, 0.088 mmol, 76% yield): LCMS=470.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.23 (2 H, m), 7.65-7.76 (4 H, m), 7.53-7.64 (3 H, m), 5.21 (1 H, s), 4.19 (2 H, d, J=2.86 Hz). HPLC Peak RT=9.5 min (Analytical Method A).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.Br[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][CH2:34][CH2:33][C:32]=2[CH:36]=1>C(#N)C>[CH:10]([O-:11])=[O:9].[O:35]1[C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N+:1]34[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]3)[C@@H:3]([O:9][C:10]([C:12]3([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[CH2:2]4)=[CH:36][C:32]=2[CH2:33][CH2:34]1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: BrCCc1ccc2c(c1)CCO2
Solvent: CC#N
Product: O=C(O[C@H]1C[N+]2(CCc3ccc4c(c3)CCO4)CCC1CC2)C1(c2ccccc2)CCCCCC1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 70 %

Procedure:
A mixture of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (126 mg) and 5-(2-bromo-ethyl)-2,3-dihydro-benzofuran (105 mg, 0.46 mmol) in acetonitrile (1.5 mL) was stirred at room temperature for 22 h. The volatiles were evaporated and the residue purified by silica gel chromatography eluting with dichloromethane then 5% then 10% MeOH/dichloromethane. The relevant fractions were combined and evaporated and the residue triturated with dichloromethane to give an off -white foam. Further purification was achieved by reverse-phase HPLC (5-98% MeCN containing 0.1% formic acid) to give the title compound (70 mg) as a white gummy solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH:5]=[CH:4]1)[CH3:2].Cl.ClCl.[C:11]([O-:16])(=[O:15])[C:12]([O-:14])=[O:13]>O>[C:11]([OH:16])(=[O:15])[C:12]([OH:14])=[O:13].[CH2:1]([N:3]1[CH2:7][CH:6]2[O:13][CH:5]2[CH2:4]1)[CH3:2]
Reactant: CCN1C=CCC1
Reactant: O=C([O-])C(=O)[O-]
Agent: Cl
Agent: ClCl
Solvent: O
Product: CCN1CC2OC2C1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 61 g. (0.63 mole) of 1-ethylpyrroline, 50 ml. of concentrated aqueous hydrochloric acid and 600 ml. of water was treated with chlorine gas for 2.5 hr. The mixture was filtered through cotton and the filtrate was washed with two 100-ml. portions of methylene chloride. The aqueous layer was made basic with 20% sodium hydroxide, heated on a steam bath for 0.5 hr. and extracted with three 100-ml. portions of methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated and the residue vacuum distilled to give 39.4 g. (56%) of the epoxide as a clear oil (b.p. 75°-90° @28 mm.). The epoxide was converted to the oxalate and the salt was recrystallized from absolute ethanol to give white needles, m.p. 142°-4° d.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:19])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:25]=[O:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([F:19])([C:14]2[S:15][C:16]([CH2:25][OH:26])=[CH:17][N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2nccs2)CC1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CO)s2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) and stirred solution of 4-fluoro-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.65 g, 12.7 mmol) in THF (20 mL) was added n-BuLi (1.33 mL, 1.05 eq., 10.0 M in hexanes). The mixture was stirred at this temperature for 30 minutes. Then a suspension of paraformaldehyde (383 mg, 1 eq.) in THF (10 mL) was added in. The resulting mixture was continued to stir at −78° C. for another 30 minutes and gradually warmed to room temperature overnight. The reaction was quenched by addition of water (10 mL). The mixture was extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (60% EtOAc in hexanes) to afford the desired product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH:11](O)=[O:12]>>[CH:11]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:12]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=CO
Product: NC(=O)c1cccc(NC=O)c1
Yield: 68 %

Procedure:
10 gm of 3-aminobenzamide and 80 ml of 98 to 100% formic acid were refluxed for 60 minutes. The formic acid was removed by evaporation under vacuum; the residual oily product was mixed with water and evaporated to yield a solid residue. This solid was crystallized from water to give 8.2 gm (yield=68%) of white, round crystals with a melting point of 176° C. to 177° C. Mass spectrum analysis indicated a molecular weight of 164.
Reaction SMILES: [Mg].II.Br[CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8].ClC[C@@H](C)CC.[CH3:16][Si:17](Cl)([Cl:19])[Cl:18]>C(OCC)C.CCCCCC.O1CCCC1>[CH3:16][Si:17]([CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8])([Cl:19])[Cl:18]
Reactant: CC[C@H](C)CBr
Reactant: C[Si](Cl)(Cl)Cl
Agent: CC[C@H](C)CCl
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](C)C[Si](C)(Cl)Cl

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (9.5 g, 0.41 mol) and molecular sieves 4A which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. (S)-(+)-1-bromo-2-methylbutane (4.5 g, 0.03 mol) was added dropwise to the slowly stirred mixture. In addition, (S)-(+)-1-chloro-2-methylbutane (36 g, 0.34 mol) was added dropwise to the stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing methyltrichlorosilane (80 g, 0.54 mol) in anhydrous diethyl ether (150 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 2° C.-5° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:22][O:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14]
Reactant: CI
Reactant: COC1=CC(=O)C(O)(CCC(C)C)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=CC(=O)C(CCC(C)C)(OC)c2ccccc21
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of Example 11A (40 mg, 0.154 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added 60% wt sodium hydride (24.6 mg, 0.616 mmol). The reaction solution was stirred for 0.5 h and methyliodide (0.038 mL, 0.616 mmol) was added. The solution was stirred 16 h at room temperature, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) afforded the title compound as a white solid (35.4 mg, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.55-0.65 (m, 1H), 0.68 (dd, J=6.80 Hz, 6H), 0.85-1.00 (m, 1H), 1.20-1.33 (m, 1H), 1.56-1.96 (m, 2H), 2.76-2.86 (s, 3H), 3.96-4.02 (s, 3H), 5.48-5.84 (s, 1H), 7.25-7.70 (m, 3H), 7.82 (d, J=7.72 Hz, 1H); MS m/z 274.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[NH2:15]>CC(O)C>[ClH:1].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[NH:15][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: Nc1ccc(OCc2ccccc2F)c(Cl)c1
Solvent: CC(C)O
Product: Cl
Product: Fc1ccccc1COc1ccc(Nc2ncnc3ccsc23)cc1Cl
Yield: 82 %

Procedure:
4-Chlorothieno[3,2-d]pyrimidine (0.103 g, 0.60 mmol) and 3-chloro-4-(2-fluorobenzyloxy)aniline (prepared according to the published method: WO 96/09294) (0.197 g, 0.78 mmol) were reacted in 2-propanol (4.5 ml) for 4.5 hours, according to Procedure A. The product was obtained as cream prisms (0.208 g, 82%) with m.p. 231-233° C.; (Found: C, 53.39; H, 3.30; N, 9.79. C19H13ClFN3OS.HCl.H2O requires: C, 53.47; H, 3.42; N, 9.85%); δH [2H6]-DMSO 8.88 (1H, s, 2-H), 8.47 (1H, d, J 7, 6 H or 7 H) 7.88 (1H, d, J 5, 2′-H), 7.55-7.68 (3H, m), 7.33-7.49 (2H, m), 7.20-7.30 (2H, m) (6H or 7H, 5′-H, 6′-H, 3″-H, 4″-H, 5″-H, 6″-H), 5.29 (2H, s, CH2); m/z 385 (M+1+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[C:13]([C:18]1[CH:30]=[C:29]([C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])[CH:28]=[CH:27][C:19]=1[O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])([CH2:16][CH3:17])([CH3:15])[CH3:14].[Cl-].[NH4+].O>C(#N)C.C(O)(C)C>[NH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][C:22](=[O:23])[CH:21]([O:20][C:19]2[CH:27]=[CH:28][C:29]([C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[CH:30][C:18]=2[C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])[CH2:25][CH3:26])=[C:3]([OH:12])[CH:4]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)cc1O

Procedure:
20 g of 2-amino-4-chloro-5-nitrophenol was dispersed in 150 ml of acetonitrile to which 37.7 g of 2-(2,4-di-tert-amylphenoxy)butanoyl chloride was added dropwise under refluxing. After refluxing for 4 hours, the reaction mixture was cooled to deposit crystals. The crystals were collected by filtration, washed with acetonitrile and dried to yield 49.5 g thereof. 49 g of the crystals were refluxed with stirring for 1 hour together with 28 g of reduced iron powder, 2.7 g of ammonium chloride, 50 ml of water and 500 ml of isopropanol. After removing the iron powder by filtration, the filtrate was cooled to deposite the crystals. The crystals were collected by filtration and dried to obtain 42.4 g of the above described compound.