Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4].[NH2:27][CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CCO>[CH2:33]([O:32][C:30](=[O:31])[C:29]([CH3:36])([CH3:35])[CH2:28][NH:27][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4])[CH3:34]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (23 mg, 0.07 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (38 mg, 0.26 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 20 mg. 1H NMR (CDCl3, 200 MHz): δ=8.36 (d, 1H, J=9.0 Hz), 8.29 (t, 1H, J=6.2 Hz), 7.55-7.47 (m, 1H), 7.42-7.39 (m, 1H), 7.33-7.22 (m, 1H), 7.20-6.98 (m, 3H), 4.23 (q, 2H, J=7.0 Hz), 3.80 (s, 3H), 3.60 (d, 2H, J=6.2 Hz), 1.36 (t, 3H, J=7.0 Hz), 1.29 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:25]2=[S:26])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(Cl)cc1NCCCNCC(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1N1CCCN(CC(C)C)C1=S
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
To an ice-cold solution of the diamine of Step A (5.0 g) and triethylamine (5.2 mL) in dry chloroform (50 mL) under nitrogen was added thiophosgene (1.5 mL). After 5 minutes at ambient temperature, additional thiophosgene (1.0 mL) was added. After 10 minutes the reaction was quenched with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a pale brown solid which was triturated with diethyl ether to give the title product (2.8 g, 48.1%) as a white solid, m.p. 96-98° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][C:22]=4[O:33][CH3:34])[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:13]=2)[CH:9]=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:31][CH2:32]5)=[CH:23][C:22]=4[O:33][CH3:34])[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1cc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(2-methoxy-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (180 mg. 0.267 mmol) was alkylated using (S)-2-methyloxirane (47 mg, 0.802 mmol), DIPEA (207 mg, 1.604 mmol) and ethanol (5 mL) to get 120 mg (crude) of the titled compound. MS: m/z=695.2 (M+1).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH3:16].Cl.Cl.[NH2:26][OH:27]>O>[CH2:15]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:3](=[O:5])[CH:2]=[N:26][OH:27])=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCc1ccc(N)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(NC(=O)C=NO)cc1
Temperature: 80 °C

Procedure:
A mixture of chloral hydrate (26.48 g, 160 mmol), anhydrous sodium sulfate (381 g, 2.68 mol), and 4-ethylaniline (18.6 mL, 150 mmol) in water (910 mL) at 80° C. was treated sequentially with concentrated HCl (20 mL) and a solution of hydroxylamine hydrochloride (31.8 g, 458 mmol) in water (150 mL). The mixture was heated to 80° C. for 1 hour, cooled to room temperature, and filtered. The filter cake was dried under vacuum to provide the desired product. MS (DCI) m/e 193 (M+H)+, 211 (M+NH4)+.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2.Br[CH2:30][C:31]([O:33]CC)=[O:32]>C1COCC1.O.[OH-].[Na+]>[CH3:7][C:8]1[N:9]([CH2:30][C:31]([OH:33])=[O:32])[C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2[nH]c(C)c(Oc3ccc(S(C)(=O)=O)cc3)c2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c(Oc1ccc(S(C)(=O)=O)cc1)c(C)n2CC(=O)O
Reaction time: 0.17 h

Procedure:
Sodium t-butoxide (220 mg) was added to a solution of the product from step (iii) (600 mg) in THF (20 ml) and stirred for 10 min. Ethyl bromoacetate (250 μl) was added and the reaction stirred for a further 1 h. The mixture was then diluted with water (10 ml), 1M aqueous sodium hydroxide (5 ml) added and stirred for 3 h. The mixture was extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified using reverse phase preparative chromatography (eluent MeCN/NH3(aq)) to give the title compound. Yield 450 mg.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[C:13]([C:21]([CH3:29])([CH3:28])[O:22][SiH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=1[O:30][CH2:31][O:32][CH3:33])=[O:5].Br[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=1>>[C:24]([SiH2:23][O:22][C:21]([CH3:29])([CH3:28])[C:13]1[C:12]([O:30][CH2:31][O:32][CH3:33])=[C:11]([CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:4]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)=[O:5])[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=1)([CH3:25])([CH3:27])[CH3:26]
Reactant: COCOc1ccc(Br)cc1
Reactant: COCOc1cc(C2CCCC2C(=O)N(C)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Product: COCOc1ccc(C(=O)C2CCCC2c2cc(OCOC)cc(C(C)(C)O[SiH2]C(C)(C)C)c2OCOC)cc1
Yield: 76.4 %

Procedure:
Use conditions analogous to those described in Step E of Examples 1A and 1B to couple (±)-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2,5-bis-methoxymethoxy-phenyl]-cyclopentanecarboxylic acid methoxy-methyl-amide (0.622 g, 1.25 mmol) and 1-bromo-4-methoxymethoxy-benzene (0.543 g, 2.50 mmol). Purify the material by silica gel chromatography eluting with Hex:EtOAc (90:10) to afford the subtitled product (0.549 g, 76%) as an oil. 1H NMR (CDCl3) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.90 (s, 9H), 1.72-1.77 (m, 1H), 1.91-2.12 (m, 4H), 2.21-2.30 (m, 1H), 3.38 (s, 3H), 3.43 (s, 3H), 3.59 (s, 3H), 3.80-3.87 (m, 1H), 4.18-4.25 (m, 1H), 4.55 (dd, J=13.6, 44.7 Hz, 2H), 4.89 (dd, J=5.9, 7.5 Hz, 2H), 4.95 (dd, J=6.6, 20.3 Hz, 2H), 5.12 (dd, J=6.8, 7.9 Hz, 2H), 6.61 (d, J=3.0 Hz, 1H), 6.75 (d, J=3.0 Hz, 1H), 6.81 (d, J=8.9 Hz, 2H), 7.63 (d, J=8.9 Hz, 2H).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[N:6][C:5]=2[NH:4][C:3]1=[O:13].CC(O)=O>CC#N.[Zn]>[O:13]=[C:3]1[NH:4][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:11]#[N:12])[C:10]=2[CH2:2]1
Reactant: N#Cc1ccnc2c1C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: N#Cc1ccnc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3,3-dibromo-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (4 g) in CH3CN (75 mL) was added AcOH (2 mL) followed by Zinc dust (4, 63 mmol). Mixture was stirred for 2 h at RT and was filtered. Solvent was evaporated and MeOH was added. A solid precipitated, which was filtered and dried.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)OC.[CH:8]1[C:9]([C:30]([F:33])([F:32])[F:31])=[CH:10][C:11]([Cl:29])=[C:12]([N:15]2[N:19]=[C:18]([C:20]#[N:21])[C:17]([S+:22]([O-:27])[C:23]([F:26])([F:25])[F:24])=[C:16]2[NH2:28])[C:13]=1[Cl:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:20]([C:18]1[C:17]([S:22]([C:23]([F:24])([F:25])[F:26])=[O:27])=[C:16]([N:28]=[CH:3][O:2][CH3:1])[N:15]([C:12]2[C:13]([Cl:14])=[CH:8][C:9]([C:30]([F:31])([F:33])[F:32])=[CH:10][C:11]=2[Cl:29])[N:19]=1)#[N:21]
Reactant: COC(OC)OC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A substantial molar excess of trimethylorthoformat is reacted with fipronil (Compound IV) at reflux with 0.5 equivalents of paratoluensulfonic acid to provide 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (Compound III).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[O:10][CH:11]1[CH:15]([CH:16]=O)[CH2:14][CH:13](OC)O1>CC(O)=O>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:13]=[CH:14][C:15]([CH:11]=[O:10])=[CH:16]2)=[CH:4][CH:3]=1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: Nc1ccc(I)cc1
Solvent: CC(=O)O
Product: O=Cc1ccn(-c2ccc(I)cc2)c1
Yield: 100 %

Procedure:
A solution of 4-iodoaniline (0.684 g, 3.12 mmol) and 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (90%, 0.492 mL, 3.12 mmol) in HOAc (10 mL) was stirred at 90° C. for 1 h. The solvent was removed in vacuo. The residue was partitioned between EtOAc and H2O. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, and concentrated in vacuo to give 1-(4-iodophenyl)-1H-pyrrole-3-carbaldehyde (0.927 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(Cl)cc4Cl)cc2CCO3)CC1

Procedure:
2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and N-methylpiperazine were reacted by General Procedure B to give 359. NMR: (CDCl3): 2.40 (3 H, s, Me), 2.49-2.58 (4 H, br m), 3.06-3.09 (2 H, m), 3.38 (3 H, s, Me), 3.49-3.90 (4 H, br m), 4.26-4.29 (2 H, m), 6.83 (1 H, s, Ar), 7.02 (1 H, d, J 8.2, Ar), 7.25 (1 H, dd, J 8.3 and 1.9, Ar), 7.31 (1 H, d, J 8.4, Ar), 7.37 (1 H, dd, J 8.4 and 2.2, Ar) and 7.55-7.57 (2 H, m, Ar). MS: (ESI+) MH+=530.13
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][C:15]#[C:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.C[N:33](C=O)C.N>CCO>[F:31][C:2]([F:1])([F:30])[CH2:3][N:4]=[C:5]([NH2:33])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][C:15]#[C:16][CH2:17][NH2:18])[N:8]=1
Reactant: CN(C)C=O
Reactant: O=C1c2ccccc2C(=O)N1CC#CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Agent: N
Solvent: CCO
Product: NCC#CCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobut-2-ynylthio)pyrimidine (0.37 g.), DMF (10 ml.), saturated ethanolic ammonia (1 ml.), EtOH (10 ml.) and yellow mercuric oxide (0.32 g.) was stirred at room temperature for 2 hours and then filtered and the filtrate evaporated to dryness. The residue was treated with EtOH (20 ml.) and 98% hydrazine hydrate (1 ml.) and the mixture heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N aqueous HCl and then filtered, The filtrate was basified with 10 N aqueous NaOH and the mixture extracted four times with ether. The combined extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobut-2 -ynylthio)pyrimidine (0.17 g.) characterised as the bis hydrogen maleate, m.p. 153°-155° (decomp.)
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[C:4]([N+:20]([O-])=O)[C:3]=1[NH:23][C@@H:24]1[CH2:29][C@@H:28]2[CH2:30][C@@H:26]([C:27]2([CH3:32])[CH3:31])[C@H:25]1[CH3:33].[H][H]>CO.[C].[Pd]>[NH2:20][C:4]1[C:3]([NH:23][C@@H:24]2[CH2:29][C@@H:28]3[CH2:30][C@@H:26]([C:27]3([CH3:31])[CH3:32])[C@H:25]2[CH3:33])=[CH:2][C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:11])[N:5]=1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c([N+](=O)[O-])nn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cc(=O)n(CC(=O)NCc3ccncc3)nc1N)C2(C)C
Yield: 17.3 %

Procedure:
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (11 mg, 0.0211 mmol) in methanol (1 mL) was stirred with 10 mass % palladium-carbon (about 5 mg) in a hydrogen atmosphere at room temperature for 2.5 hours. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the desired product (1.5 mg, 17% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19](Br)=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu](C#N)[C:26]#[N:27]>CS(C)=O.[OH-].[NH4+].O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19]([C:26]#[N:27])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nc(Br)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#C[Cu]C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1nc(C#N)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To 4-[(5-bromo-3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.00125 mol) in DMSO (10 mL), under nitrogen, was added copper cyanide (0.565 g, 0.00625 mol) and the mixture heated to 150° C. for 1.5 h. The reaction mixture was cooled to rt, diluted with a mixture of 20% ammonium hydroxide in water (50 mL) and dichloromethane (50 mL) and allowed to stir for 1 h. The organic layer was removed, dried over sodium sulfate, filtered and concentrated to an oil. The oil was chromatographed on silica using a gradient of 20–40% ethyl acetate/hexane to give the title compound as a foam. M.S.(M+1): 348.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[OH2:16].[C:8]([C:7]1[C:2]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: NCCCO
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1NCCCO
Product: O

Procedure:
The procedure of Example 7 is followed to react and work up 5 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide and 8 ml 3-amino-propan-1-ol. The product is recrystallized from ethanol/water. Yield: 4.87 g (78.4% of the theoretical yield), with a melting point of 141° C.-143° C.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=O)[CH3:2].O1C=[CH:11][CH:10]=[CH:9]C1O.C(Cl)(Cl)Cl.[C:18](=O)([O-])[O-:19]>C1COCC1.CCOCC>[O:4]1[CH2:5][CH2:6][C@H:18]([OH:19])[C@@H:2]2[CH2:9][CH2:10][CH2:11][C@H:1]12
Reactant: OC1C=CC=CO1
Reactant: O=C([O-])[O-]
Reactant: C=COC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@H]1CCO[C@H]2CCC[C@H]21
Temperature: 17.5 °C

Procedure:
Racemic alcohol (±)-18 (68 mg, 0.48 mmol) was dissolved in THF (5 mL) and vinyl acetate (225 μL, 2.4 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-20° C. The mixture was left stirring for >48 h until around 50% conversion was reached (as seen by NMR). The resulting suspension was diluted with Et2O and filtered on celite, the filter cake rinsed with Et2O. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5:1, 3:1 then 1.5:1) to yield the desired enantioenriched pyranol (−)-18 (25 mg, 37%). [α]D20 −47.5 (c 1.32, CHCl3). An enantiopurity of 94.1% ee for the alcohol was measured by chiral HPLC analysis of the corresponding activated carbonate 31d: Column ChiralPak IA, 0.7 mL/min, Hexanes/IPA (98:2 to 85:15, from 0 to 45 min), λ=210 nm, T=30° C., Rt minor=22.4 min, Rt Major=23.3 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)N1CCCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of (6-chloro-pyridin-3-yl)[1,4]diazepan-1-yl-methanone (255.1 g, 1.06 mol) in dichloroethane (3.0 L) was added cyclobutanone (108.1 mL, 1.45 mol). After a 1 h aging period, sodium triacetoxyborohydride (308.2 g, 1.45 mol) was added in four equal portions over 1.5 h. The resulting mixture was allowed to stir for 20 h, then quenched with 2.5 L of an aqueous solution containing NaOH (141.3 g, 3.53 mol). After stirring for 30 minutes, the layers were separated and the organic dried with magnesium sulfate, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [F:1][C@H:2]1[C@H:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]1=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:16]([NH:23][CH:3]1[CH2:4][CH:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1C[C@@H](COCc2ccccc2)[C@@H]1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Reaction time: 0.08 h

Procedure:
In a 25 mL flask with trans-2-fluoro-3-(benzyloxymethyl)cyclobutanone (0.20 g, 0.96 mmol) inside, dry 1,2-DCE 3.4 mL was added under argon to give a colorless solution. To this, benzylamine (0.11 mL, 1.01 mmol) was added to give still a colorless solution. After stirring for 5 min, sodium triacetoxyborohydride (0.29 g, 1.37 mmol) was added all at once to give a white emulsion. Then AcOH (0.06 mL, 1.05 mmol) was added drop by drop. After 5 min, it gave a yellow solution and this was left stirring for 2 hr and then the reaction was quenched by sat. NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc twice. The combined organic phase was dried over MgSO4 and the crude product was purified by silica gel flash chromatography (Hexane: EtOAc=3:1) to give 0.19 g (65%, Rf=0.18) of the product. 1H NMR (CDCl3, 600 MHz): δ 1.81-1.95 (m, 3H), 2.80-2.89 (m, 1H), 3.46-3.56 (m, 3H), 3.76-3.84 (m, 3H), 4.51-4.55 (m, 2H), 4.89-5.00 (td, 1H, J=54.6, 4.8), 7.25-7.37 (m, 10H).
Reaction SMILES: CC1(C)CC(C[N:10]=C=O)(C)CC(N=C=O)C1.[C:17]([O:21][CH2:22][CH2:23]CO)(=[O:20])[CH:18]=[CH2:19]>>[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].[NH2:10][C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCCCO
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
A urethane acrylate was prepared with IPDI, hydroxypropyl acrylate and a 1000 MW polyether diol in an equivalent ratio of 3/2/1. The reaction product was a clear, colorless liquid. At 25° C. the viscosity was 8,000 cps.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]1[C:8]([CH3:10])([CH3:9])[C:7]([F:12])([F:11])[CH2:6][N:5]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Li+].[OH-]>CO.O>[F:12][C:7]1([F:11])[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C@H:4]([C:3]([OH:20])=[O:2])[C:8]1([CH3:10])[CH3:9]
Reactant: COC(=O)[C@H]1N(C(=O)OC(C)(C)C)CC(F)(F)C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)(F)C(C)(C)[C@H]1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of methyl ester F4 (4.7 g, 16 mmol) in methanol (100 mL) was added a solution of LiOH (6.8 g, 160 mmol) in water (50 mL) and the solution was heated at 50° C. for 14 h. The methanol was removed in vacuo and the remaining solution was diluted with water (200 mL). The aqueous solution was extracted with ether (2×200 mL), acidified with 1N HCl (200 mL) and extracted again with ether (2×200 mL). The combined organics were washed with brine (1×200 mL), dried with magnesium sulfate and concentrated in vacuo. The while solid was dried overnight at 40° C. under vacuum. Isolated yield: 4.3 g (95%). 1H NMR (400 MHz, DMSO-d6): δ 12.95 (bs, 1H), 3.93 (s, 1H), 3.84–3.74 (m, 2H), 1.38 (s) +1.33 (s) (9H), 1.19 (s, 3H), 1.01 (s, 3H); 19F NMR (376 MHz, DMSO-d6): δ −111.4 (dt, J=227, 13 Hz) +−112.4 (dt, J=227, 13 Hz) (1F), −113.5 (dt, J=227, 14 Hz) +−113.9 (dt, J=227, 15 Hz) (1F); MS-APCI (m/z+): 180.1, (m/z−): 278.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([C:42](=[O:44])[CH3:43])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: CC(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (200 mg, 0.41 mmol) was dissolved in methylene chloride (5 mL). Triethyl amine (0.173 mL, 1.24 mmol) and acetyl chloride (0.035 mL, 0.49 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and chromatography on silica gel with methylen chloride/triethyl amine 99:1 gave the desired product (122 mg, 56%) as a light yellow foam, MS: m/e=528.2 (M+H+).