Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7][CH2:8]Br.[CH3:10][O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].C1N=CN(C(N2C=NC=C2)=[O:27])C=1>CCOCC.C1COCC1>[C:12]12([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:10](=[O:27])[O:11]1)[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccccc1N
Reactant: BrCCCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccccc2C2(CCCC2)O1
Yield: 22.6 %

Procedure:
To a stirred solution of magnesium turnings (19.44 g, 800 mmol) and a catalytic amount of iodine in ether (500 mL) was slowly added 1,4-dibromobutane (24.0 mL, 200 mmol). The reaction was stirred until reflux ceased. The magnesium was decanted and the solution was slowly added to 2-aminobenzoic acid methyl ester (8.0 mL, 61.70 mmol) in THF (600 mL) at 0° C. The solution was stirred overnight at room temperature, quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The crude material was taken up in THF (150 mL) and CDI (9.17 g, 56.53 mmol) was added. The reaction mixture was stirred overnight at room temperature and partitioned between ammonium chloride solution (sat) and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 20% ethyl acetate/hexane gave spiro[4H-3,1-benzoxazine-4,1′-cyclopentan]-2(1H)-one as a white solid (2.60 g, 27%). 1H NMR (DMSO-d6): δ 10.15 (s, 1H), 7.28 (m, 2H), 7.03 (t, J=7.6 Hz, 1H), 6.89 (dd, J=7.9, 0.8 Hz, 1H), 2.15 (m, 2H), 2.07 (m, 2H), 1.90 (m, 4H); MS (ESI) m/z 204 ([M+H]+); Anal. calcd for C12H13NO2: C, 70.92; H, 6.45 N, 6.89. Found: C, 70.84; H, 6.42; N, 6.77.
Reaction SMILES: Br[C:2]1([C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]2[CH:8]=[CH:9][N:10]=[C:5]2[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:3]1.[N:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1[O:42][CH3:43])=[C:30]=[O:31].CN(C=O)C>ClCCl>[CH3:43][O:42][C:33]1[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:32]=1[NH:29][C:30]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:2]2[N:3]=[C:4]([N:11]3[CH:15]=[CH:14][N:13]=[C:12]3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:23]=1)=[O:31]
Reactant: Nc1cccc(C2(Br)Cn3ccnc3C(n3ccnc3-c3ccncc3)=N2)c1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccncc3)n2)c1
Yield: 89.1 %

Procedure:
A solution of 3-[6-Bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (400 mg), 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (246 mg), in dichloromethane (DCM) (3 ml) and DMF (0.5 ml) is stirred at room temperature for 16 hr. The mixture is concentrated in vacuo, the residue slurried with diethyl ether/methanol (20:1), and filtered to give 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-{3-[8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea (6) (468 mg) as a white solid.
Reaction SMILES: N(C[C@H]1CCNC[C@H]1O)=[N+]=[N-].C(N(CC)CC)C.FC1C([O:26][C:27]([C:29]2[N:30]=[N:31][C:32]([CH2:48][CH2:49][CH2:50][CH3:51])=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:37][CH:36]=3)[CH:34]=2)=O)=C(F)C(F)=C(F)C=1F.CCOC(C)=O>COCCOC>[CH2:48]([C:32]1[N:31]=[N:30][C:29]([CH:27]=[O:26])=[CH:34][C:33]=1[C:35]1[CH:36]=[CH:37][C:38]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:39][CH:40]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [N-]=[N+]=NC[C@H]1CCNC[C@H]1O
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C=O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
To a solution of cis-4-azidomethyl-piperidin-3-ol (1.4 mmol, 272 mg) in DME (4.2 mL) was added triethylamine (5.62 mmol, 0.8 mL) and 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (1.41 mmol, 785 mg). Reaction was stirred at room temperature for 3 h. Upon completion, the reaction was quenched with 0.1N NaOH (40 mL), extracted, dried and removal of solvent afforded the residue which was chromatographed with hexane:EtOAc gradient to afforded (±)-cis-4-azidomethyl-3-hydroxy-piperidin-1-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (180 mg, 25% yield).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32](=[O:34])[CH3:33])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 89 %

Procedure:
A mixture of 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (400 mg, 0.85 mmol) in ethanol (6 mL), tetrahydrofuran (4 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at reflux for 48 h. The mixture was diluted with ethyl acetate (200 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-ethanone (250 mg, 89%) as a white solid: LC/MS m/e calcd for C22H22N2O [M+H]+ 331.43, observed 331.0.
Reaction SMILES: [O-]C#[N:3].[Na+].N1C=CC=CC=1.[CH3:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=O)(C)(C)C>C(#N)C>[NH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:27]([NH:3][S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=1)(=[O:20])=[O:19])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cccc(S(=O)(=O)NC(=O)NCCCCCCN)c1
Reaction time: 4 h

Procedure:
To a suspension of 0.47 sodium cyanate in 20 ml acetonitrile was added 0.42 g pyridine and 0.95 g m-methylphenylsulfonylchloride and the mixture was agitated in an ultrasound bath under argon for ca 1 h. The resulting suspension was added to a solution of 0.500 g N-mono-tert.butyloxycarbonylhexamethylenediamine in 10 ml acetonitrile and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between dichlormethane and 1N sodium hydroxide. The phases were separated and the aqueous phase was acidified by addition of citric acid and extracted with dichloromethane. The second organic phase was washed with half concentrated brine and purified by chromatography on silica gel with heptane:ethyl acetate=1:1. The product fractions were collected and evaporated. The residue was taken up in 5 ml trifluoro acetic acid and kept at room temperature for 4 h. The solvent was evaporated and the residue was taken up in methanol and purified by chromatography on silica gel with a gradient of dichloromethane:methanol:ammonia=19:1:0.1 to 7:3:0.2. The product fractions were concentrated under aspirator vacuum whereby crystallisation occurred. The product was recrystallized from methanol to yield 0.180 g of the title compound as white crystals melting at 186.7-187.4° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:9](O)=O.Br[C:21]1[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:8]([C:9]2[NH:28][C:23]3[C:24]([N:27]=2)=[N:25][CH:26]=[CH:21][CH:22]=3)[CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)c1cc(O)cc(OCc2ccccc2F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Oc1cc(OCc2ccccc2F)cc(-c2nc3ncccc3[nH]2)c1

Procedure:
Reaction of 3-(2-fluorobenzyloxy)-5-hydroxybenzoic acid (3.9 g, 15 mmole, 1.0 eq.) with 5-bromo-2,3-diaminopyridine (5.6 g, 30 mmole, 2 eq.), HBTU (11.3 g, 30 mmole, 2 eq.) and TEA (5.2 mL) in DMF (40 mL) over 18 h gave the amide intermediate (LC/MS calculated and found (M+2H+)=434 and 416 final product). This intermediate was isolated by pouring the reaction mixture into 400 g of ice water and filtering the subsequent white solid which formed. After the solid was thoroughly dried to 6.2 g, the material was brought through to the next step. The solid (2 g) was dissolved in 10 mL of ethyl alcohol and 10 mL of glacial acetic acid and put in the microwave at 180° C. for 30 min. This was repeated two more times to bring all 6.2 g through to the final product. This product crashed out of solution and was isolated as a brown solid after cooling the mixture to 0° C. for 10 h. The light tan solid (5.6 g) had an LC/MS with a calculated and found (M+H+)=416.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([N:15]([CH3:16])[C:12]3[CH:13]=[CH:14][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]4)=[CH:10][CH:11]=3)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)S(=O)(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.9 %

Procedure:
D3 (100 mg, 0.31 mmol) and triethylamine (65 ul, 0.47 mmol) were combined in dry DCM (3 mL) under argon. 4′-Fluoro-4-biphenylsulfonyl chloride (93 mg, 0.34 mmol) was added dropwise in a solution of dry DCM (3 mL). The reaction mixture was stirred at room temperature under argon for 19 h and diluted with DCM (20 mL) and washed with water then the organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material was purified by chromatography eluting with 0-100% Et2O/petroleum ether to afford the title compound (53 mg), δH (CDCl3), 400 MHz: 1.23 (3H, d), 1.46 (9H, s), 2.01 (1H, m), 2.14, 1H, dd), 2.57 (1H, m), 2.74 (1H, m), 3.10 (1H, m), 3.21 (3H, s), 3.39-3.51 (2H, AB), 3.81 (1H, d), 4.19 (1H, br.s), 7.08 (2H, d), 7.17 (2H, t), 7.28 (2H, m), 7.57 (2H, dd), 7.61 (4H, s). MS (ES+): MH+ 554.3
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@@H:13]([OH:26])[C@@H:14]2[NH:24][CH3:25])[CH2:6]1)(=O)C.O>CO.[OH-].[K+]>[Cl:28][C@:7]12[CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21][C@:20]1([CH3:23])[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C@@H:14]([NH:24][CH3:25])[C@H:13]([OH:26])[CH2:12]3)[CH2:9][C@H:8]2[Cl:27]
Reactant: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3C[C@@H](Cl)[C@@]4(Cl)C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3C[C@@H](Cl)[C@@]4(Cl)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A stirred suspension of 5α,6β-dichloro-17β-methylamino-5α-androstane-3β,16α-diol 3-acetate (13 g) in methanol (105 ml) and aqueous potassium hydroxide solution (3.9 ml; 10 N) was heated under reflux for 1 hr., cooled and water was added to precipitate the product as a white solid, which was filtered off, and washed with water (wt. 11 g). Recrystallisation of a sample from methanol gave 5α,6β-dichloro-17β-methylamino-5α-androstane-3β,16α-diol as prisms, m.p. 194°-195° C. (decomp.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:31]OC1C=CC=CC=1NC.O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[CH3:31])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNc1ccccc1OC
Reactant: COc1ccccc1Nc1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Product: COc1ccccc1N(C)c1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-((2-methoxyphenyl)(methyl)amino)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenylamino)pyridin-2-yl)cyclopropanecarboxamide by reacting 2-methoxy-N-methylaniline with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)SC)#[N:2].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[C:1]([NH:3][C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[N:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: NCCCCCO
Solvent: c1ccncc1
Product: N#CNC(=NCCCCCO)NCCCCCO

Procedure:
Heating dimethyl N-cyanodithioimidocarbonate with an excess of 5-aminopentan-1-ol in pyridine gives N-cyano-N',N"-bis(5-hydroxypentyl)guanidine, which may be treated with p-toluenesulphonyl chloride in pyridine and the product heated with thiourea in acetone to give N-cyano-N',N"-bis(5-(S-isothioureido)pentyl)guanidine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]#[CH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]#[CH:11])[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCNCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(Cc1ccccc1)C(=O)C(C)(C)C

Procedure:
To a stirred solution of N-benzylprop-2-yn-1-amine (472 mg, 3.25 mmol) and triethylamine (493 mg, 4.88 mmol) in DCM (16 mL), cooled to 0° C. was added pivaloyl chloride (451 mg, 3.74 mmol). After 1 hour the reaction mixture was applied directly to the top of a silica gel column for purification, eluting with a gradient of 60-100% DCM in hexanes to give the title compound. MS: m/z=230 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:9][CH:10]=2)[N:7]=1.C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:10][N:9]=1
Reactant: Fc1ccccc1Cc1ncc2ccc(Cl)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccccc1Cc1ncc2cccnn12

Procedure:
2.004 g of palladium on carbon (5%) were initially charged under argon, and 20.04 g (76.58 mmol) of the compound obtained in Example 3A in ethyl acetate (750 ml) were then added. 21.348 ml (153.159 mmol) of triethylamine were then added, and the reaction mixture was hydrogenated at standard hydrogen pressure and 20° C. for 16 hours. The same amount of catalyst as indicated above was then added, and the reaction mixture was hydrogenated at standard hydrogen pressure and 20° C. for another night. The mixture was then filtered through Celite, the filter cake was washed with ethanol and the filtrate was concentrated and dried under high vacuum. This gave 22.79 g of the target compound (about 100% of theory, contaminated with triethylamine).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[O:9])=[O:5])[CH3:2].C[C:21]1([CH3:30])[CH2:26]C(O)[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1.[CH3:31][C:32]([CH3:35])([O-])[CH3:33].[K+]>C1(C)C=CC=CC=1>[CH3:31][C:32]1([CH3:35])[CH2:33][CH:1]([O:3][C:4]([CH2:6][N:7]([CH2:14][C:15]([O:17][CH:18]2[CH2:29][C:23]([CH3:24])([CH3:28])[NH:22][C:21]([CH3:26])([CH3:30])[CH2:19]2)=[O:16])[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[O:9])=[O:5])[CH2:2][C:21]([CH3:30])([CH3:26])[NH:22]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCC(=O)N(CC(=O)OCC)CC(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCC(=O)N(CC(=O)OC1CC(C)(C)NC(C)(C)C1)CC(=O)OC1CC(C)(C)NC(C)(C)C1
Yield: 152.8 %

Procedure:
To the same reactor as in Example 1 were added 23.3 g (0.09 mole) of N,N-bis(ethoxycarbonylmethyl)butanecarboxylic acid amide, 28.2 g (0.18 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 50 ml of toluene and 0.5 g (0.04 mole) of potassium tert-butoxide. Reaction and after-treatment were carried out in the same manner as in Example 1 to obtain 30.3 g of N,N-bis(2,2,6,6-tetramethyl-4-piperidinyloxycarbonylmethyl)butanecarboxylic acid amide as a white crystal (yield, 70%). Melting point, 96°-98° C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)OCCC2=O
Yield: 58.5 %

Procedure:
7-tert-Butyl-chroman-4-ol (assumed 32.1 mmol) was taken up in dichloromethane (250 mL) and with stirring was added PCC (14.36 g, 2eq) portion-wise. After the addition was complete, the resulting mixture was stirred for about 3 hours by which time the reaction was complete by TLC analysis. About 250 mL of hexanes were added to the mixture and it was then filtered through a pad of celite and the filtrate was concentrated. Purification by column chromatography on silica gel eluting with a gradient of 2% ethyl acetate in hexanes to 10% ethyl acetate in hexanes afforded the title compound as an off-white solid (3.838 g) (M+H)+=205.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[N-:25]=[N+:26]=[N-:27].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[N:25]([CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1)=[N+:26]=[N-:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CN=[N+]=[N-])c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (2.00 g, 4.76 mmol) in N,N-dimethylformamide is treated with sodium azide (0.325 g, 5.00 mmol), stirred overnight at room temperature, treated with 18-crown-6, stirred at room temperature for two hours, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]([N+:20]([O-])=O)[CH:17]([CH3:19])[CH3:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Fe]>[NH2:20][CH:16]([C:13]1([OH:15])[CH2:12][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[O:10])[CH2:14]1)[CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)C([N+](=O)[O-])C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 0.34 mmol) was taken into 4:1 THF:water (5 mL) followed by addition of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) and the mixture was heated to reflux. After four hours additional aliquots of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) were added and the mixture was allowed to reflux an additional 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate then filtered. The filtrate was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate then the organic layer washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents to give a residue (36.5 mg) that was further purified by preparative reverse phase HPLC to give 3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol trifluoroacetate salt (7.9 mg) as a colorless amorphous solid after lyophilization of the combined pure fractions. 1H-NMR (400 MHz, D6-DMSO): 8.63 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H), 7.35-7.31 (m, 1H), 7.17 (q, 1H), 6.71-6.66 (m, 1H), 4.23 (dd, 1H), 4.03 (dd, 1H), 3.80 (dd, 1H), 3.66 (dd, 1H), 2.34 (dd, 1H), 1.79-1.70 (m, 1H), 0.84-0.77 (m, 6H). MS (EI) for C20H21F3IN3O2: 520 (MH+).
Reaction SMILES: [C:1]12([C:11]([O:13][CH:14]3[CH:18]4[O:19][C:20](=[O:26])[CH:21]5[CH:22]([C:23](O)=[O:24])[CH:15]3[CH2:16][CH:17]45)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)(=O)C([Cl:30])=O>C1(C)C=CC=CC=1>[C:1]12([C:11]([O:13][CH:14]3[CH:18]4[O:19][C:20](=[O:26])[CH:21]5[CH:22]([C:23]([Cl:30])=[O:24])[CH:15]3[CH2:16][CH:17]45)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Product: O=C(Cl)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
In 420 ml of toluene was suspended 60 g of the carboxylic acid (23) obtained in Synthesis Example 1-1-2. At 80° C., 25.3 g of oxalyl dichloride was added dropwise to the suspension, which was stirred for 4 hours. The toluene was distilled off in vacuum, obtaining the target compound. The resulting acid chloride was used in the subsequent reaction without further purification.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:26][O:27][CH3:28])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][CH3:20])[N:17]([S:21]([O-:24])(=[O:23])=[O:22])[C:16]2=[O:25])=[O:13])[N:10]=1)=O.[Na+:29].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:26][O:27][CH3:28])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][CH3:20])[N:17]([S:21]([O-:24])(=[O:23])=[O:22])[C:16]2=[O:25])=[O:13])[N:10]=1.[Na+:29]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 0.15 g of the above-mentioned sodium (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine-1-sulfonate in 4ml of water is added under ice-cooling 0.044 g of sodium monomethyldithiocarbamate, and the mixture is stirred for one hour at room temperature. The same procedure as Example 3B yields 0.057 g of sodium (3R,4S)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine-1-sulfonate.