Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH:11]1([CH2:16][C@H:17]([CH2:21][NH:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:1]=[O:2])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
Under a nitrogen atmosphere, formic acid (192 mL, 5 mol) was dissolved in CH2Cl2 (450 mL) and cooled to 0° C. Acetic anhydride (73 mL, 0.77 mol) was then added, and the reaction mixture was stirred for 45 min. After this time, a solution of (2R)-3-cyclopentyl-2-({[(phenylmethyl)oxy]amino}methyl)propanoic acid (22.85 g crude material, assumed 77.1 mmol) in CH2Cl2 (450 mL) was added, and the resulting mixture was stirred for 1.5 h at 0° C. The volatiles were then removed, the crude residue was dissolved in EtOAc (500 mL), and the mixture was washed with brine (4×100 mL). The organics were dried (MgSO4) and concentrated to provide (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (23.5 g, 100%) as a thick syrup. LCMS: (M+H)+: 306.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])C.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[CH3:33]>>[Br:23][C:8]1[N:9]([CH:20]([CH3:21])[CH3:22])[C:10]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[CH3:33])=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1
Reactant: Cc1cc(C#N)ccc1N
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: Cc1cc(C#N)ccc1NC(c1ccc(Cl)cc1)c1c(C(=O)O)nc(Br)n1C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 4-amino-3-methylbenzonitrile. The reaction mixture was stirred at rt for 20 h. The mixture was extracted with HCl 1M and with a saturated aqueous NaHCO3 solution. The organic layers were dried (Na2SO4), filtered and concentrated. The product was triturated in Et2O, the suspension was filtered and the solid was dried in HV. tR: 1.30 min (LC-MS 2); ESI-MS: 515.2/517.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[S:10][C:11]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.O>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:19][NH2:20])[S:10][C:11]=2[S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of 2-{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (0.53 g) in ethanol (5 mL) was added hydrazine monohydrate (0.1 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 0.36 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>O1CCOCC1.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:34][OH:33])[CH:40]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Temperature: 160 °C
Yield: 45.8 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 (21.0 mg, 0.096 mmol) and [3-(hydroxymethyl)phenyl]boronic acid (30.0 mg, 0.193 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (9.7 mg, 46%).
Reaction SMILES: C[N:2]([CH3:7])[CH:3]=[CH:4][CH:5]=[O:6].Cl.[Cl:9][C:10]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12](=O)CN.CC[O-].[Na+].Cl>C(O)C>[CH:5]([C:4]1[C:12]([C:11]2[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:10]=2[Cl:9])=[CH:7][NH:2][CH:3]=1)=[O:6]
Reactant: CN(C)C=CC=O
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
5.4 g of 3-dimethylaminoacrolein, 3.2 g of 2,3-dichlorophenacylamine hydrochloride and 60 ml of ethanol are heated for 11/2 hours under reflux. Then a solution of sodium ethylate in ethanol (prepared from 1 g of sodium and 15 ml of ethanol) is added dropwise and the reaction mixture is heated under reflux for another 30 minutes. After it has cooled to room temperature, the reaction mixture is poured onto ice/water and neutralised with hydrochloric acid. The precipitate is washed with water, dried in vacuo, and the dry residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/ethyl acetate). M.p. 152°-154° C. IR (solid/KBr) in cm-1 : 1655 (CO). 1H-NMR (CDCl3) in ppm: 7.0 (broad s, 1H); 7.3 (m, 2H); 9.66 (s, 1H); 11.9 (s, 1H, H replaceable with D2O). Mass peak at 204. This substance is novel, has fungicidal activity, and falls within the ambit of the invention.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.Cl.[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][C:34](O)=[O:35])[CH3:30].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:35])[CH2:33][CH2:32][N:31]([CH2:37][CH3:38])[CH2:29][CH3:30])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CCN(CC)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-(diethylamino)propionic acid hydrochloride (0.0032 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(diethylamino)-1-propanone (0.025 g, 0.00005 mol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:16](=N)(N)[CH3:17].C([O-])(=O)C.[Na+]>O>[CH3:16][C:17]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11](=[O:12])[NH:13][N:14]=1
Reactant: NNC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1n[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Yield: 34 %

Procedure:
A mixture of 4 parts of N-(4-nitrophenyl)hydrazinecarboxamide, 5 parts of ethanimidamide hydrochloride and 5 parts of sodium acetate is stirred and heated for 4 hours at 140° C. The reaction mixture is cooled, water is added and the whole is stirred till the product is crystallized. It is filtered off and recrystallized from 2-propanol, yielding 1.5 parts (34%) of 2,4-dihydro-5-methyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one; mp. 226.1° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[I-].[Na+].O>C(#N)C>[C:20]([O:19][C:17](=[O:18])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-(4-fluorobenzoyl)piperidine hydrochloride (0.5 g, 2.01 mmol) was suspended in acetonitrile (5 mL), 4-(Boc-amino) Butyl Bromide was added (0.569 g, 2.01 mmol) and sodium iodide (0.461 g, 3.02 mmol) and the mixture was stirred at 80° C. overnight. Water was added and the aqueous phase was extracted with 30 mL dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrated concentrated and purified with column chromatography on silica using dichloromethane/Methanol (95/0.5) to yield 0.830 g, (2.1 mmol, 100% yield) of the title compound as a brown solid. MS (m/e): 379.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Reactant: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Combined ethyl 2-(4-cyanophenyl)acetate (25 g, 0.132 mol) with DMF-DEA (60 mL) and heated to 70° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated and then purified by flash chromatography to give the title compound (20 g, 62%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (d, J=8.4 Hz, 2H), 7.59 (s, 1H), 7.29 (d, J=8.4 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 2.67 (s, 6H), 1.13 (t, J=6.8 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=1[N+:18]([O-])=O.[H][H]>[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:14])=[O:15])=[C:8]([OH:17])[C:7]=1[NH2:18]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1O
Agent: [Pd]
Product: Nc1c(N2CCCO2)cc(Cl)c(S(N)(=O)=O)c1O
Yield: 94.6 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-isoxazolidinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.84 g, 2.7 mmol) was reduced with hydrogen and 10% Pd/C (0.84 g) to form the desired product (0.75 g crude). LC-MS m/z 279(M+).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])C.[CH3:15][CH:16]([NH:18][CH2:19][CH2:20][OH:21])[CH3:17].C1(C)C=CC=CC=1>CCOCC>[CH3:15][CH:16]([N:18]([CH2:19][CH2:20][OH:21])[C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:17]
Reactant: CC(C)NCCO
Reactant: CCOC(=O)c1noc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(CCO)C(=O)c1noc2ccccc12
Temperature: 140 °C
Yield: 81.6 %

Procedure:
A mixture of ethyl-1,2-benzisoxazole-3-carboxylate (10.0 g), 2-(1-methylethylamino)ethanol (16.1 g) and toluene (80 ml) was heated to 140° C. in a bomb for 4 hrs. The solution was diluted with ether (50 ml), washed with 5% sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 60% ethyl acetate in hexanes to give 10.6 g (81.4%) of product. Recrystallization from dichloromethane/hexanes afforded the analytical sample, mp 92°-94° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([OH:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][C:25]([O:24][CH3:23])=[O:26])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)c(O)c2ncccc12
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c(Br)cc(C(C)=O)c2cccnc12

Procedure:
26.6 g of 5-acetyl-7-bromo-8-hydroxyquinoline are dissolved in 200 ml of tetrahydrofurane, 11 g of triethylamine are added and 9.5 g of chloroformic acid methyl ester, diluted in 50 ml of tetrahydrofurane, are added dropwise, whilst stirring and cooling. When the exothermic reaction has ended, the triethylamine hydrochloride which has separated out is removed by filtration and the clear filtrate is evaporated.
Reaction SMILES: O[Li].O.[CH2:4]([N:11]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:12]1[C:27]([N:29]([CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35]C)=[O:34])[CH3:30])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OS([O-])(=O)=O.[K+]>O.C1COCC1>[CH2:4]([N:11]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:12]1[C:27]([N:29]([CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([OH:35])=[O:34])[CH3:30])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C(C)(C)CN(C)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(C)(C)C(=O)O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of LiOH H2O (214 mg, 5.11 mmol) in H2O (3 mL) was added to a stirred solution of methyl 3-(1-benzyl-3-(4-chlorophenyl)-N-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamido)-2,2-dimethylpropanoate (259 mg, 0.511 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. An extra portion of LiOH H2O (107 mg, 2.55 mmol) was added, followed by the addition of H2O (11 mL) and THF (11 mL). The reaction mixture was stirred at room temperature for 2 d and then acidified with aqueous 0.5 M KHSO4 (10 mL). The product was extracted with DCM (3×20 mL). The organic layers were combined and washed with brine (3×10 mL). The combined organic layers were dried on Na2SO4 and filtered. Solvents were removed in vacuo to give the desired product (233 mg, 93%) as a white foam.
Reaction SMILES: [OH:1][C@:2]1([C:9]#[N:10])[C@H:7]2[CH2:8][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[ClH:11]>C1COCC1>[ClH:11].[ClH:11].[NH2:10][CH2:9][C@@:2]1([OH:1])[C@H:7]2[CH2:8][N:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: N#C[C@]1(O)CN2CC[C@@H]1C2
Agent: Cl
Solvent: C1CCOC1
Product: NC[C@]1(O)CN2CC[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3R,4R)-3-Hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile (390 mg, 2.82 mmol) was dissolved in THF (1 mL). Borane-THF complex was added (2.9 ml, 2.90 mmol) and the mixture was allowed to stir for 20 min, at which time an additional portion of Borane-THF complex (5.7 ml, 5.70 mmol) was added and the mixture brought to reflux for 3 h. The reaction mixture was cooled to ambient temperature and carefully quenched with 5 ml EtOH followed by 0.5 ml water and allowed to stir overnight. The mixture was evaporated to dryness and azeotroped with EtOH, re-dissolved in acetone (10 mL) and to this was carefully added 3N HCl (10 mL, 30 mmol). The effervescent reaction was allowed to stir for 2 hours, at which time bubbling had ceased and the reaction was evaporated to near-dryness and azeotroped several times with EtOH, at which point the product began to crystallize from solution. After ˜5 cycles of azeotroping, the residue was suspended in EtOH and solids were collected by filtration to afford (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (br. s., 1H) 8.27 (br. s., 3H) 6.29 (s, 1H) 2.86-3.63 (m, 9H) 2.14-2.37 (m, 1H) 1.64-2.05 (m, 1H). Optical rotation (4.01 mg/mL, water)=−15.01°.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12]C=O)[CH2:10][C:9]2=[CH:15][CH:16]=[CH:17][C:7]3=[C:8]2[N:3]1[CH2:4][CH2:5][CH2:6]3.C(O)C.CCOCC.[ClH:26]>>[ClH:26].[O:1]=[C:2]1[CH:11]([NH2:12])[CH2:10][C:9]2=[CH:15][CH:16]=[CH:17][C:7]3=[C:8]2[N:3]1[CH2:4][CH2:5][CH2:6]3
Reactant: O=CNC1Cc2cccc3c2N(CCC3)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC1Cc2cccc3c2N(CCC3)C1=O

Procedure:
A solution of N-(2,3,6,7-tetrahydro-3-oxo-1H,5H-benzo(ij)quinolizin-2-yl)-formamide (0.8 g, 3.4 mmol) in ethanolic hydrogen chloride (10 mL of 4.2 M) was heated at 50° C. for 2 hours. The ethanol was cooled, an equal volume of ether was added, and the precipitate was filtered off and washed with ether to give 0.78 g of 2,3,6,7-tetrahydro-3-oxo-1H,5H-benzo(ij)quinolizin-2-amine hydrochloride, mp 216°-221° C. The product was recrystallized for analysis; mp 219°-222° C. Anal. Calcd. for C12H14N2O.HCl: C, 60.37; H, 6.33; Cl, 14.85; N, 11.74. Found: C, 59.89; H, 6.42; Cl, 15.41; N, 11.68.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]=1[CH3:23])=[O:8].N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.Cl>[C:30]1([S:36]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:11]=2[CH3:23])=[O:8])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the carboxamide (0.304 mmol) of step 1 above in dichloromethane (5 mL) in a 25 ml round bottom flask was added pyridine (0.304 mmol) and benzenesulfonyl chloride (0.304 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with hydrochloric acid (2N) and extracted with dichloromethane (2×15 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layers were then dried with magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown oil. The oil was further purified by silica gel chromatography using 5% ethyl acetate in hexanes as the mobile phase to yield ′3-[(phenylsulfonyl)amino]-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)thiophene-2-carboxamide as a white to yellow solid.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[C:6]([F:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][OH:4].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1.C(=O)(O)[O-].[Na+]>COC(OC)(C)C>[CH3:19][C:18]1([CH3:23])[O:1][C@H:2]([C:5]2[C:6]([F:16])=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][O:4]1
Reactant: CCOC(=O)c1cccc([C@@H](O)CO)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: O
Product: CCOC(=O)c1cccc([C@@H]2COC(C)(C)O2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A 5.71 g portion of ethyl 3-[(1R)-1,2-dihydroxyethyl]-2-fluorobenzoate was dissolved in 30 ml of 2,2-dimethoxypropane, mixed with 476 mg of p-toluenesulfonic acid monohydrate and stirred at room temperature for 30 minutes. This was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.46 g (81%) of ethyl 3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorobenzoate (Reference Example 16-1). FA: 269
Reaction SMILES: [CH2:1]([C:4]1([CH3:22])[O:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[CH:14][C:5]1=2)[CH:2]=[CH2:3].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([C:4]1([CH3:22])[O:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[CH:14][C:5]1=2)[C:2]1[CH:3]=[CH:2][CH:1]=[CH:4][CH:3]=1
Reactant: C=CCC1(C)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A mixture of 1-(4-amino-3-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared using 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to Procedure C, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ 10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H), MS (ESI) m/z 364 ([M+H]+, 100%), Anal. Calc. For C22H18ClNO2: C, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N, 3.58.