Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:25][CH:26]([CH3:28])[CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:25][CH:26]([CH3:27])[CH3:28])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(OC(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1nc2ccc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 12 step B from 6-chloro-4-(2-chloro-benzyl)-2-isopropoxy-quinoline-3-carboxylic acid ethyl ester and 1N NaOH. Off white solid. LC-MS (ESI): 390 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C([O:14][C:15](=[O:33])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1/[CH:25]=[C:26]1/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/1)C>>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]([OH:33])=[O:14])=[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)=[O:4])[C:27]2=[O:32])[CH:20]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(CC(=O)c2ccc(Cl)cc2)C1=O

Procedure:
Prepared from 2-bromo-1-(4-chlorophenyl)ethanone and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16 (yield: 8.2 mg, 34%): LC/MS (an10p8): Rt 2.8 min, m/z 510 [M−H]−. 1H NMR (DMSO-d6): δ 3.01-3.09 (m, 1H), 3.57-3.63 (m, 1H), 4.79 (s, 2H), 5.17 (s, 2H), 5.21-5.24 (m, 1H), 6.91-6.95 (m, 1H), 7.44 (m, 2H), 7.66-7.69 (m, 2H), 8.07-8.09 (m, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH2:42][CH2:43][CH2:44][Cl:45])[CH:32]=2)[N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH2:42][CH2:43][CH2:44][Cl:45])[CH:32]=2)[N:19]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1OCCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCN)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reaction time: 1 h
Yield: 120.4 %

Procedure:
methyl 4-((4-((8-((tert-butoxycarbonyl)amino)octyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-(3-chloropropoxy)benzoate (280 mg, 0.422 mmol) was dissolved in TFA (1 mL, 12.98 mmol) and DCM (2 mL). The reaction was stirred for 1 h. The solvent was removed under vacuum to give 286 mg (100%) methyl 4-(4-(8-aminooctylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-(3-chloropropoxy)benzoate, TFA which was used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][O:24]CC4C=CC=CC=4)[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][OH:24])[O:17]3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(COCc1ccccc1)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: [H][H]
Solvent: CO
Product: O=C(CO)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Yield: 23518.9 %

Procedure:
(R)—N-(7-Benzenesulfonyl-chroman-2-ylmethyl)-2-benzyloxy-acetamide (100 mg, 0.22 mmol) and Perlman's catalyst (12 mg) were added to 15 mL MeOH and hydrogenated for 18 hours at 1.5 atmospheres of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give 18.7 g of (R)—N-(7-Benzenesulfonyl-chroman-2-ylmethyl)-2-hydroxy-acetamide, MS (M+H)=362.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]1[C:17]([OH:19])=O.[CH3:20][N:21]1[C:25]([NH2:26])=[N:24][N:23]=[N:22]1>N1C=CC=CC=1>[CH3:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]1[C:17]([NH:26][C:25]1[N:21]([CH3:20])[N:22]=[N:23][N:24]=1)=[O:19]
Reactant: Cn1nnnc1N
Reactant: Cn1c(C(=O)O)cc2cccnc2c1=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cn1nnnc1NC(=O)c1cc2cccnc2c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 114 mg (0.96 mmol) of thionyl chloride are added to 150 mg (0.74 mmol) of 7-methyl-1,7-naphthyridin-8(7H)-one-6-carboxylic acid and 110 mg (1.1 mmol) of 1-methyl-5-aminotetrazole in 3 ml of pyridine. The mixture is stirred at RT for 16 h. The reaction is then quenched with a little water, the pyridine is evaporated and the residue is purified by HPLC. Yield 27 mg (13%).
Reaction SMILES: F[C:2](F)(F)[CH2:3][NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.F[C:23](F)(F)CN>>[CH3:2][CH:3]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=12)[CH3:23]
Reactant: NCC(F)(F)F
Reactant: OC(CNCC(F)(F)F)COc1cccc2ccccc12
Product: CC(C)NCC(O)COc1cccc2ccccc12
Temperature: 100 °C
Yield: 68 %

Procedure:
(RS)-1-(2,2,2-TRIFLUOROETHYLAMINO)-3-(1-NAPHTHYLOXY)-2-PROPANOL ##STR2## A mixture of (2RS)-1'-(2,3-epoxypropoxy)naphthalene (1.4 g, 6.49 mmole) and 2,2,2,-trifluroethylamine (25 g, 252.4 mmole) were heated in a sealed glass tube for about 115 hours at 100° C., Excess amine was distilled under vacuum and collected. The remaining solid was dissolved in ether and washed twice with 250 ml of water. The ethereal solution was treated with dry hydrogen chloride gas to convert the amine to its hydrochloride salt which is collected as a off white solid ; m.p. 178°-180° C.; (yield 68%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.O.Cl.Cl.[CH:19]1([CH2:29][CH2:30]N2CCN(C3C=CC=CC=3OC)CC2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][O:20]1>>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:29][CH:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][O:20]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: O
Product: Clc1cccc(N2CCN(CCC3OCCc4ccccc43)CC2)c1

Procedure:
Following the general procedure of EXAMPLE 1 and making non-critical variations but using 1-(3-chlorophenyl)piperazine dihydrochloride (XI, 0.5169 g (1.92 mmol) in place of 1-(2-chlorophenyl)piperazine dihydrochloride (XI), the title compound is obtained, mp 176.75°-179°; MS (m/z) 356; IR (mineral oil) 2269, 2295, 2166, 2130, 2200 and 1449 cm-1.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC(C=O)=CC=1>C(O)C>[N:8]1[CH:13]=[CH:12][C:11]([CH:1]=[CH:2][C:3]([OH:5])=[O:4])=[CH:10][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: c1ccncc1
Agent: O=Cc1ccncc1
Solvent: CCO
Product: O=C(O)C=Cc1ccncc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.6 %

Procedure:
To a mixture of malonic acid (12 g), pyridine (7.6 g) in ethanol(41 ml) was added dropwise 4-pyridinecarbaldehyde (10.3 g) at 40° C. The mixture was stirred at 80° C. for 5 hours, then cooled to room temperature. The precipitate was filtered washed with ethanol and dried in vacuo to give 3-(4-pyridyl)-2-propenoic acid (10.4 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>O1CCOCC1>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:10]=[CH2:11])[N:3]=1
Reactant: COc1cccc(Br)n1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1cccc(OC)n1
Temperature: 100 °C

Procedure:
step 1—A mixture of 2-bromo-6-methoxypyridine (5.00 g), tributylvinyltin (9.30 mL), and PdCl2(PPh)3 in dioxane (100 mL) in a sealed tube was heated overnight at 100° C. The reaction was cooled to RT and the volatile organics were removed under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 10% EtOAc) to afford 2.00 g of 2-methoxy-6-vinyl-pyridine (24) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:26]([CH3:28])[CH3:27]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:26]([CH3:28])[CH3:27])[CH2:18][CH2:17]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:7]([CH:23]=1)[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9])#[N:2].B(Br)(Br)Br.O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:7]([CH:23]=1)[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9])#[N:2]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(C#N)ccc2Oc2cccc(F)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc(C#N)ccc1Oc1cccc(F)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.6 %

Procedure:
To a stirred solution of methyl 4-((1S)-1-{[5-cyano-2-(3-fluorophenoxy)benzoyl]amino}ethyl)benzoate (step 2, 200 mg, 0.47 mmol) in dichloromethane (10 mL) was added a solution of boron tribromide (1 M in dichloromethane, 0.95 mL, 0.95 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was poured into water (10 mL) and the whole was extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 62 mg (33%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 12.86 (1H, br.s), 8.95 (1H, d, J=7.9 Hz), 8.04 (1H, d, J=2.2 Hz), 7.90 (1H, dd, J=8.6, 2.2 Hz), 7.81 (2H, d, J=8.3 Hz), 7.51–7.40 (3H, m), 7.12–6.90 (4H, m), 5.07 (1H, m), 1.37 (3H, d, J=6.9 Hz); MS (ESI) m/z 405 (M+H)+, 403 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.[CH3:47][N:48](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:47]#[N:48])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Temperature: 120 °C
Yield: 66 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was charged with compound 138 (200 mg, 0.300 mmol), tetrakis(triphenylphosphine)pallasium (34.0 mg, 0.029 mmol), zinc cyanide (70 mg, 0.60 mmol) and anhydrous DMF (1 mL). The vial was purged with nitrogen, heated to 120° C. for 3.5 h then cooled to ambient temperature and poured into a saturated aqueous sodium bicarbonate solution (25 mL). The resulting suspension was extracted with methylene chloride (3×20 mL), and the organic extracts were combined, dried over sodium sulfate and filtered. Concentration of the filtrate followed by purification by column chromatography gave a 66% yield of compound 141 as a white solid. 1H NMR (CDCl3) δ (ppm) 8.30 (d, 1H, J=6.9 Hz), 7.58-8.02 (m, 7H), 7.30 (d, 1H, J=7.0 Hz), 5.60 (s, 2H), 5.07 (bs, 1H), 3.65 (m, 2H), 2.84 (s, 3H), 1.58 (d, 3H, J=6.7 Hz), 0.96 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:6])=[O:5].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH2:16]1>N1C=CC=CC=1.Cl>[ClH:6].[ClH:6].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[N:26]=[C:25]([NH:27][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH2:16]1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 55 °C
Yield: 49 %

Procedure:
Add 2,4,6-trifluorobenzoyl chloride (117 mg, 0.60 mmol) to a solution of 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 1 (preparation 10, 100 mg, 0.46 mmol) in pyridine (6 mL) and heat at 55° C. overnight. Re-add another portion of 2,4,6-trifluorobenzoyl chloride (50 mg, 0.26 mmol) and heat at 65° C. for 4 hr. Remove volatiles under reduced pressure, dissolve the residue in 1N HCl, extract twice with ethyl ether. Adjust aqueous layer to pH>11 with 5N NaOH. Extract the aqueous layer there times with DCM. Combine organic layers, dry over sodium sulfate, filter and concentrate to give a residue. Purify the residue by chromatography (silica gel, 5% 2M NH3/MeOH in DCM) to provide the free amine of the title compound as a colorless oil (84 mg, 49%): MS (ion spray): m/z=376.2 (M+H)+; 1H NMR (CDCl3): δ 8.91 (s, br, 1H), 8.20 (d, 1H), 7.73 (t, 1H), 7.14 (d, 1H), 6.71 (m, 2H), 6.61 (m, 1H), 2.65 (m, 1H), 2.44 (m, 3H), 2.35 (s, 6H), 2.12 (m, 2H), 1.53 (m, 1H). Using a salt formation method similar to that in example 1 provides the di-hydrochloride salt. Di-hydrochloride salt: Anal. cal'd for C20H20F3N3O.2HCl: C, 53.58; H, 4.95; N, 9.37. Found: C, 53.42; H, 4.91; N, 9.23.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[C:9](=[O:10])[N:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:1]3[C:5]4=[N:6][C:7]5[CH2:13][CH2:12][CH2:11][C:8]=5[C:9](=[O:10])[N:4]4[CH:3]=[CH:2]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=c1c2c(nc3[nH]ccn13)CCC2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccn3c(=O)c4c(nc23)CCC4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,6,7,8-tetrahydro-5H-cyclopent[d]imidazo[1,2-a]pyrimidin-5-one (0.345 g, 1.967 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (0.0650 g, 2.10 mmol) in DMF (15.0 ml)-DMSO (5 ml) was added potassium carbonate (0.30 g, 2.17 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was purified by preparative TLC (methylene chloride: methanol=20:1) to provide a colorless amorphous solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:30][C:26]([S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:27][N:28]=3)[CH2:32][CH2:33]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Product: CCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC3CCCC3)CC2)s1
Yield: 77 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-ethanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 32(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 77%). MS (m/e): 528.3 (M+H+, 35%), 545.4 (M+NH4+, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]1[CH:24]=[CH:23][C:22]2[CH:25]([CH2:29][CH2:30]O)[CH2:26][CH2:27][CH2:28][C:21]1=2.C(Cl)(Cl)(Cl)[Cl:33].C(#N)C>>[Cl:33][CH2:30][CH2:29][CH:25]1[C:22]2[CH:23]=[CH:24][S:20][C:21]=2[CH2:28][CH2:27][CH2:26]1
Reactant: OCCC1CCCc2sccc21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: ClCCC1CCCc2sccc21
Reaction time: 3 h
Yield: 56 %

Procedure:
Triphenylphosphine (3.94 g, 15 mmol) is added to a solution of 2-(4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)ethanol (2.74 g, 15 mmol) in Cl4C/Acetonitrile 1:1 (20 mL) at room temperature and the mixture is maintained under stirring for 3 hours monitoring the reaction by TLC. The solution is concentrated to half the volume at reduced pressure, CH2Cl2 is added and washed with water. The organic phase is separated and evaporated to dryness. The crude is treated with diethyl ether and the precipitate is filtered. The diethyl ether is evaporated to dryness, and the resulting crude is purified by column chromatography, giving 4-(2-chloroethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene (1.7 g, 8.4 mmol, 56%, oil). 1H NMR (300 MHz, CDCl3): δ 1.54 (m, 1H), 1.79 (m, 1H), 1.92 (m, 3H), 2.20 (m, 1H), 2.77 (m, 2H), 3.00 (m, 1H), 3.64 (m, 2H), 6.86 (d, J=5.2 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: Nc1ccccc1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 6.9 grams (0.033 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 3.08 grams (0.033 moles) aniline. The reaction mixture was stirred for three days at room temperature. The solid mass that formed was slurried in pentane and filtered. The filter cake was air dried and weighed 9.2 grams (92% crude yield). The product melted at 169°-171° C. with decomposition and the infrared spectrum of the product contained a strong carbonyl band at 1650 cm-1 and a sharp NH band at 3320 cm-1 and the isocyanate band at 2225 cm-1 of the starting material was absent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C=O)cc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (0.5 g, 4.1 mmol), 1-bromopropane (0.3 ml) and K2CO3 (0.69 g, 5 mmol) in anhydrous DMF (5 ml) was stirred for 1 h at reflux. This was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.55 g, 82.3%), as yellow oil 1H-NMR (CDCl3) 1.0 (tr, 3H, J=7.41 Hz); 1.7-2.0 (m, 2H); 3.95 (tr, 2H, J=6.57 Hz); 6.95 (d, 2H, J=8.73 Hz); 8.00 (d, 2H, J=8.76 Hz).
Reaction SMILES: C(O)C.[CH3:4][N:5]1[C:9]([S:10][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[CH:22]([NH:23][C:24](=[O:39])[C:25]([C:33]4[N:34]=[C:35]([NH2:38])[S:36][CH:37]=4)=[N:26][O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])[C:21](=[O:40])[N:16]3[C:17]=2[C:18]([OH:20])=[O:19])=[N:8][N:7]=[N:6]1.C(=O)(O)[O-].[Na+:45]>O>[CH3:4][N:5]1[C:9]([S:10][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[CH:22]([NH:23][C:24](=[O:39])[C:25]([C:33]4[N:34]=[C:35]([NH2:38])[S:36][CH:37]=4)=[N:26][O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])[C:21](=[O:40])[N:16]3[C:17]=2[C:18]([O-:20])=[O:19])=[N:8][N:7]=[N:6]1.[Na+:45]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1

Procedure:
1 ml of ethanol was added to a solution of 0.162 g of the product of Example 36 in 0.3 ml of a molar solution of sodium bicarbonate in water and the mixture was vacuum filtered. The filtrate was evaporated to dryness undere reduced pressure and the residue was taken up in ethanol. After efflorescence, the mixture was vaccum filtered to obtain 0.09 g of the syn isomer of sodium 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:24][S@@](C(C)(C)C)=O)[CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[NH2:24][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13]
Reactant: CC(C)(C)[S@@](=O)N[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(F)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: N[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N—((S)-2-(3-bromo-5-fluorophenyl)-2-((R)-1,1-dimethylethylsulfinamido)ethyl)-2-nitrobenzenesulfonamide (3.55 g, 6.80 mmol) in Et2O (22.65 mL), and HCl (4 M in dioxane) (3.40 mL, 13.59 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized by Na2CO3 solution and extracted by EtOAc. The organic layer was washed with water, dried, filtered off, and concentrated in vacuo providing the crude (S)—N-(2-amino-2-(3-bromo-5-fluorophenyl)ethyl)-2-nitrobenzenesulfonamide, which was used in next step reaction without further purification. LCMS (m/z): 418.2/420.2 (MH+), 0.62 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([OH:22])[CH:19]=2)[C:14]1=[O:24])[CH2:10][CH2:11][CH3:12]>CN(C)C=O>[Br:1][C:19]1[C:18]([OH:22])=[C:17]([F:23])[CH:16]=[C:15]2[C:20]=1[CH2:21][CH:13]([CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC1Cc2cc(O)c(F)cc2C1=O
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(cc(F)c(O)c2Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
N-Bromosuccinimide (1.41 g, 7.93 mmol) was added to a solution of 2-butyl-6-fluoro-5-hydroxy-1-indanone (1.76 g, 7.93 mmol) in anhydrous N,N-dimethylformamide (15 mL). The resulting solution was stirred at room temperature for two hours. The solvent was evaporated under vacuum and the residue was partitioned between EtOAc (100 mL) and water (100 ml). The organic phase was washed with water (4×100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide crude 4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone (2.17 g) as an oil.