Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5](Br)[CH2:6][CH3:7])[CH3:2].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(Br)CC
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)OCc1ccccc1

Procedure:
As per scheme-12, ethyl-2-bromobutyrate (12-a) is reacted with benzyl alcohol in presence of potassium hydroxide in DMF at 25° C. to 35° C. up to 3 hr to provide ethyl-2-benzyloxybutyrate (12-b). Compound 12-b is treated with hydrazine hydrate in ethanol at reflux temperature to provide corresponding acid hydrazide compound 12-c. The compound 12-c is treated with 2-picolinic acid in the presence of dehydrating agent EDC along with HOBt and N-methyl morpholine in DMF at a temperature 0° C. to 30° C. for 1 hr to provide uncyclized compound 12-d. The compound 12-d is further treated with Lawesson's reagent in tetrahydrofuran at a reflux temperature for 4 hr to provide corresponding pyridinyl-1,3,4-thiadiazolyl compound 12-e. The compound 12-e is stirred with borontribromide in dichloromethane at a temperature ranging from 0° C. to 5° C. for 1 hr followed by at 35° C. for overnight, to provide corresponding pyridinyl-1,3,4-thadiazolyl propanol compound 12-f. The compound 12-f is treated with p-nitrophenylsulfonyl chloride in the presence triethylamine in a dichloromethane at a temperature ranging from 0° C. to 15° C. to provide corresponding p-nitrophenyl sulfonic acid ester compound 12-g.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:30][CH2:29][C@:12]34[C:13]5[C:14]6[O:28][C@H:11]3[C@@H:10]([NH:31][CH3:32])[CH2:9][CH2:8][C@@:7]4([OH:33])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41]>N1C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[CH2:30][CH2:29][C@:12]34[C:13]5[C:14]6[O:28][C@H:11]3[C@@H:10]([N:31]([CH3:32])[S:43]([CH2:42][C:37]3[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=3)(=[O:45])=[O:44])[CH2:9][CH2:8][C@@:7]4([OH:33])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:2][CH2:3]1
Reactant: CN[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O[Si](C)(C)C(C)(C)C)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CN([C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O[Si](C)(C)C(C)(C)C)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
203.9 mg of 17-cyclopropylmethyl-3-tert-butyldimethylsilyloxy-14β-hydroxy-4,5α-epoxy-6α-(methylaminomorphinan 108 obtained in reference example 91 was dissolved in 3 ml of pyridine followed by the addition of 124 mg of 3,4-dichlorophenylmethanesufonylchloride and stirring for 30 minutes at room temperature. After concentrating the reaction system, 3 ml of saturated aqueous sodium bicarbonate and 3 ml of chloroform were added to separate layers, after which the aqueous layer was extracted twice with 3 ml of chloroform. After drying with anhydrous sodium sulfate, the organic layer was concentrated to obtain the oily crude product. This was then purified with silica gel column chromatography (30 g benzene/ethyl acetate=5/1) to obtain 235.4 mg of the target compound (yield: 78%).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:31]1[C:32]2[CH2:39][C:38](=[O:40])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CCN(C(C)C)C(C)C>CC(O)C>[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:31]4[C:32]5[CH2:39][C:38](=[O:40])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:28][CH2:29]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Fc1ccc(-c2cn(CCN3CCCC3)c(C3CCNCC3)n2)cc1F
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2c(ncnc2N2CCC(c3nc(-c4ccc(F)c(F)c4)cn3CCN3CCCC3)CC2)N1
Yield: 15.6 %

Procedure:
Combine 4-(4-(3,4-difluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl)-piperidine tris hydrochloride (0.3 g; 0.00065 mol), 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g; 0.00083 mol), DIPEA, (1.00 mL, 0.0057 mol) into IPA (9 mL) and heat in a microwave at 80° C. for 1 h; cool and concentrate. Quench with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA and purify by column chromatography using 0-10% MeOH/DCM as eluent to give the title compound (0.05 g; 15.67%). MS (ES+): m/z=494 (M+1).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[CH2:13]([NH:19][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCCCCN
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CNCCCCCNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1,5-pentanediamine affords N,N'-(1,5-pentylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)5, Z = H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]3[NH:25][N:24]=[N:23][N:21]=3)[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(Oc2c(C)nn(CC#N)c2C)c2c1CCC2
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)nn(Cc3nnn[nH]3)c2C)c2c1CCC2
Temperature: 95 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a stirred solution of [4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile (3.0 gm, 0.0101 mole) in Dimethylformamide (30 ml), Sodium azide (1.2 gm, 0.0185 mole) and Triethylamine hydrochloride (4.0 gm, 0.0303 mole) were added at room temperature (27-30° C.). The reaction mixture was stirred at 90-100° C. for 4 hours. The reaction mixture was cooled and poured into dilute Hydrochloric acid (100 ml) and stirred for 30 minutes. The separated solid was filtered and dissolved in Ethyl acetate (100 ml). The Ethyl acetate layer was dried over Sodium sulphate and distilled under vacuum to get a 1.5 gm of desired product as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][C:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)(O)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[Cl:27][C:22]1[CH:21]=[C:20]([C:16]2[CH2:17][CH2:18][C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:14][CH:15]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1ccc(Cl)c(Cl)c1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2=CCC3(CCNCC3)CC2)cc1Cl
Yield: 104.9 %

Procedure:
9-(3,4-Dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (547 mg, 1.32 mmol) was dissolved in trifluoroacetic acid (25 mL) and heated to reflux over night. Ethyl acetate was added and the reaction mixture was basified with sodium hydroxide (2 N). The aqueous phase was extracted three times with ethyl acetate and the combined organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated to give 410 mg (100%) of 9-(3,4-dichloro-phenyl)-3-aza-spiro[5.5]undec-8-ene as a white gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[CH:6][CH2:7][CH2:8][CH3:9])[CH3:2].[N+:11]([CH3:14])([O-:13])=[O:12].N12CCCN=C1CCCCC2>>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH:6]([CH2:14][N+:11]([O-:13])=[O:12])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCCC=CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Yield: 99.4 %

Procedure:
To a stirred solution of hex-2-enoic acid ethyl ester (A) (450 g, 3.164 mol, 1 eq) in nitromethane (858 ml, 15.822 mol, 5 eq) cooled at 0° C., is added dropwise, under nitrogen, 481.8 g (3.164 mol, 1 eq.) of 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture is allowed to react at room temperature for 3 h and is quenched with a 6M aqueous hydrogen chloride solution to obtain pH=4. The solution is extracted with diethyl ether (500 ml+2×300 ml). The organic layers are dried with MgSO4, filtered and concentrated to obtain an oil residue (672.13 g, HPLC purity=78.9%) which is purified by liquid chromatography eluting with dichloromethane. 639.41 g of 3-nitromethyl-hexanoic acid ethyl ester (B) are obtained (yield=99.4%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Yield: 72.7 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 3-amino-4-chlorophenol (422 mg, 2.93 mmol), potassium carbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) was stirred using a microwave synthesizer at 180° C. for 30 min. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=17/83→75/25) to give the title compound (610 mg, 73%) as a brown powder.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH2:19][CH2:18]3)=[O:12])=[CH:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3c2NCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
To a solution of 95 mg (0.22 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amide in 2 ml conc. acetic acid 46 mg of sodium borohydride (0.67 mmol) were added in three portions (ice bath cooling). The reaction mixture was stirred for 3 h at rt, then treated with 2N NaOH to adjust the pH to 12, extracted twice with diethylether and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:4) to give 45 mg white foam (45%). MS(ISP) 431.5 (M+H)+.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:29])([OH:28])[OH:27])[C@@H:21]([OH:30])[C@H:20]1[OH:31])(=O)C1C=CC=CC=1.[NH4+].[OH-]>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:27])([OH:28])[OH:29])[C@@H:21]([OH:30])[C@H:20]1[OH:31]
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)[C@@H](O)[C@H]1O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
Compound 24.3 (43 mg, 0.961 mmol) was treated with concentrated NH4OH (4.85 mL, 0.02 M) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was treated with 1% AcOH (2 mL). Reverse phase HPLC afforded compound 24.4 (23 mg, 70% yield) as a white solid: 1H NMR (D2O, 300 MHz) 8.21 (s, 1H), 8.11 (s, 1H), 6.41 (m, 1H), 5.97 (d, J=5.7 Hz, 1H), 5.84 (m, 1H), 4.66 (appt t, J=4.8 Hz, 1H), 4.53 (m, 1H), 4.22 (t, J=4.8 Hz, 1H); 31P NMR (D2O, 121.4 MHz) 9.4; MS (ESI) m/z 344 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)(=O)=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1
Product: c1ccc(COc2cccc(CCCn3ccnc3)c2)cc1
Yield: 44 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(3-benzyloxyphenyl)propyl methanesulfonate was allowed to react with imidazole to give 1-[3-(3-benzyloxyphenyl)propyl]imidazole. The yield was 44%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 82-83° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N+:17]([O-])=O)[C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:17][C:8]1[C:9]([CH3:16])=[C:10]([CH:15]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COCCOc1cc(C(=O)OC)c(C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COCCOc1cc(N)c(C)c(C(=O)OC)c1
Temperature: 80 °C
Yield: 106.4 %

Procedure:
To stirred solution of methyl 5-(2-methoxyethoxy)-2-methyl-3-nitrobenzoate (1.35 g, 4.83 mmol) in ethanol (20 mL) were added ammonium chloride (1.35 g, 25.0 mmol) dissolved in water (20 mL) and iron powder (1.07 g, 19.3 mmol). The resulting reaction mixture was heated at 80° C. for 3 h. On completion, the reaction mixture was filtered and the residue washed well with hot ethanol. The filtrate was concentrated and the residue was basified by aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, concentrated under reduced pressure to give the crude title compound (1.23 g) which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[O:3]1.[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCCP(=O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33]([NH:15][C:14]1[CH:13]=[N:12][N:11]([CH3:18])[C:10]=1[C@H:4]1[CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][C@@H:2]([CH3:1])[O:3]1)=[O:34]
Reactant: CC1CC(O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Pd+2]
Agent: CCCP(=O)=O
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@@H]1CC(O)CC[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
A solution of 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (79 mg, 0.30 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (0.19 mL, 50% wt in EtOAc, 0.39 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) gave 108 as a white solid (4 mg, 3% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=11.8 Hz, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.37-7.30 (m, 1H), 7.04-6.97 (m, 2H), 6.15 (s, 2H), 5.00-4.93 (m, 1H), 4.17 (s, 1H), 4.03 (dd, J=8.0, 6.9 Hz, 1H), 3.77 (s, 3H), 2.11-1.74 (m, 5H), 1.28 (d, J=3.3 Hz, 1H), 1.21 (dd, J=9.2, 6.3 Hz, 3H). Alkyl OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]([C@@H:5]1[CH2:8][C@H:7]([OH:9])[CH2:6]1)[CH3:4].C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:30]3[N:31]=[C:32]4[C:38]([C:39](O)=[O:40])=[CH:37][N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:33]4=[N:34][CH:35]=3)=[N:25][N:26]2[CH3:29])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:9][C@@H:7]1[CH2:8][C@H:5]([CH:3]([NH:2][C:39]([C:38]2[C:32]3[C:33](=[N:34][CH:35]=[C:30]([C:24]4[C:23]5[C:27](=[CH:28][C:20]([F:19])=[CH:21][CH:22]=5)[N:26]([CH3:29])[N:25]=4)[N:31]=3)[N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:37]=2)=[O:40])[CH3:4])[CH2:6]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)[C@H]1C[C@@H](O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-3-(1-aminoethyl)-cyclobutanol hydrochloride (crude from step 6, 91 mg, 0.60 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (0.24 mL, 1.36 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol), and HATU (114 mg, 0.30 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated to a pale yellow solid. Trituration with EtOAc/Et2O gave 108 mg (74%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([O:10]CC)=[O:9])[S:5][C:6]=1[Br:7].[OH-].[Li+].C1COCC1.Cl>O>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[Br:7]
Reactant: CCOC(=O)c1sc(Br)c(Br)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(Br)c(Br)c1Cl
Temperature: 25 °C
Reaction time: 32 h
Yield: 86.5 %

Procedure:
Ethyl 4,5-dibromo-3-chlorothiophene-2-carboxylate (5.52 g, 15.8 mmol) and lithium hydroxide (0.716 g, 31.7 mmol) were taken up in mixture of THF (30 mL) and water (30 mL). The reaction mixture was stirred at 25° C. for 32 hours. The aqueous layer was made acidic by the dropwise addition of conc hydrochloric acid and extracted with ether (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the product as a white solid (4.38 g, 86%) that was used without purification: mp 209-223° C. (d); 1H NMR (CDCl3 and DMSO-d6) δ 4.15 (bs, 1H); EI/MS 320 m/e (M+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[CH2:20][N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([O:24][CH:25]([CH:27]3[CH2:29][CH2:28]3)[CH3:26])=[O:23])[C@H:4]2[S:3]1>[Zn].C(O)(=O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[CH2:20][N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:22]([O:24][CH:25]([CH:27]3[CH2:28][CH2:29]3)[CH3:26])=[O:23])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CN(C(=O)OC(C)C3CC3)c3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CN(C(=O)OC(C)C3CC3)c3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
Zinc powder (3.0 g) was added under stirring at 5° C. to a solution of 2,2,2-trichloroethyl 2-methyl-7-[N-(1-cyclopropylethyoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylate (2.95 g) in a mixture of anhydrous dimethylformamido (12.5 ml) and acetic acid (3.75 ml), and the mixture was stirred for 1.5 hours. After the reaction, zinc powder was filtered off and washed with dimethylformamide (2 ml). The filtrate and the washings were combined, and the combined solution was extracted by pouring into a mixture of ethyl acetate (50 ml), ice-water (50 ml) and 10% hydrochloric acid (3 ml). The aqueous layer was further extracted with ethyl acetate (20 ml). The extract was combined, and then washed three times with water (20 ml) and once with a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the obtained residue was washed with ether and dried to give colorless crystals of 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem- 4-carboxylic acid (2.01 g), mp 168° to 169° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][C:16]#[N:17])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][C:16]#[N:17])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: N#CN=C1NCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: N#CN=C1NCCN1c1ccc(N)cc1
Yield: 95.4 %

Procedure:
3.47 g (15 mmol) of 1-(4-nitrophenyl)imidazolidin-2-ylidene cyanamide are hydrogenated in 35 ml of methanol using hydrogen on 5% palladium on carbon. Conventional work-up gives 2.88 g of 1-(4-aminophenyl)imidazolidin-2-ylidene cyanamide in the form of a pale-brown solid (ESI: 202).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH:32]=[C:31]([CH3:30])[CH:35]=[N:34]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: Cc1cn[nH]c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 43 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and 4-Methyl-1H-pyrazole (43% yield, white solid, MS (m/e): 493.1 (M+H, 100%)