Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][C@H:6]([C:13]([OH:15])=[O:14])[CH2:5]2.Cl.[CH3:17]O>>[CH3:17][O:14][C:13]([C@@H:6]1[CH2:5][C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=2)[CH2:8][NH:7]1)=[O:15]
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Agent: Cl
Product: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reaction time: 18 h

Procedure:
(S)-6,7-Dihydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (62 g), 200 mL anhydrous MeOH, and 26 mL concentrated hydrochloric acid were stirred together overnight at 70° C. The mixture was then evaporated and the residue resuspended in 500 mL acetonitrile with vigorous stirring to wash all the solid material. Stirring continued for 18 h at r.t., after which the solid product was collected by filtration, washed with 100 mL acetonitrile, and dried under vacuum overnight. Yield 77 g (quantitative). 1H NMR (400 MHz, MeOH-d4): 6.64 (s, 1H), 6.61 (s, 1H), 4.42-4.36 (m, 1H), 4.29-4.24 (m, 2H), 3.89 (s, 3H), 3.29-3.22 (m, 1H), 3.11-3.02 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21]CC)=[O:20])=[C:13]2[CH2:12][N:11]1[C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.[Li+].[OH-]>C1COCC1.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:11]2[CH:10]([CH2:9][OH:8])[CH2:15][N:14]3[N:16]=[C:17]([I:24])[C:18]([C:19]([OH:21])=[O:20])=[C:13]3[CH2:12]2)=[O:35])=[CH:32][CH:31]=1)#[N:34]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)Nc1ccc(C#N)cc1)C(CO[Si](C)(C)C(C)(C)C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2Cc3c(C(=O)O)c(I)nn3CC2CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
To a solution of Intermediate 351E (0.7 g, 1.148 mmol) in THF (10 mL) and water (5 ml) was added LiOH (0.083 g, 3.45 mmol) and the reaction mass was stirred at RT for 24 h. The volatiles were evaporated; the residue was diluted with water (10 mL) and neutralized with an aqueous solution of 1.0 N HCl. The solid product separated was filtered and dried to afford Intermediate 351F (0.4 g, 74%) as an off-white solid which was taken to the next step without further purification. MS(ES): m/z=468 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.35-12.80 (br, 1H), 9.33 (s, 1H), 7.69-7.74 (m, 2H), 7.62-7.68 (m, 2H), 5.20-5.30 (m, 1H), 5.10-5.19 (m, 1H), 4.72 (d, J=4.53 Hz, 1H), 4.46 (d, J=18.51 Hz, 1H), 4.27-4.38 (m, 2H), 3.40-3.48 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 86.3 %

Procedure:
A solution of 6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.31 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (1.42 g, 86.6%) as an amorphous solid.
Reaction SMILES: C([O:4][CH2:5][CH:6]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]1[CH3:22])[CH3:7])(=O)C.O1CCCC1.[OH-].[Na+]>CO>[C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([CH:6]([CH3:7])[CH2:5][OH:4])[C:9]=1[CH3:22])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCC(C)n1c(C)cc(C(=O)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
In 10 ml of methanol was dissolved 1.24 g (4.15 mmoles) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)-2-methylethyl acetate. Tetrahydrofuran (30 ml) and then 10 ml (10.0 mmoles) of an 1.0 N aqueous solution of sodium hydroxide was added. The mixture was stirred for 3 hours at room temperature. The solvent was distilled off under reduced pressure. The residue was extracted with 50 ml of ethyl acetate three times, and the resulting extracts were dried over anhydrous magnesium sulfate, and concentrated to afford 900 mg of a crude product. The crude product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (1/1) as an eluent to afford compound (106) (790 mg, 3.07 mmoles, 74.1%).
Reaction SMILES: CC[O-].[Na+].[Na].[CH2:6]([SH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19](Cl)=[CH:20][CH:21]=2)[N:16]=1>O.C(O)C>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([S:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: SCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Nc1ccc2ccc(SCc3ccccc3)nc2n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of sodium ethylate prepared from sodium (2.3 g) and ethanol (160 cc), benzyl mercaptan (13.6 g) is added and the mixture is stirred for 1 hour at a temperature in the region of 20° C. 2-Amino-7chloro-1,8-naphthyridine (18 g) is then added and the mixture is heated for 6 hours at 60° C. The suspension produced is poured into water (500 cc) and extracted with methylene chloride (3×250 cc). After being washed with water and dried, the organic solution is concentrated to dryness under reduced pressure (4 kPa) to give 2amino-7-benzylthio-1,8-naphthyridine (15.4 g), m.p. 167° C. EXAMPLE 11
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:5]([F:10])[C:6](=[N:8][NH2:9])[N:7]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:10])=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[N:3]=1
Reactant: NN=c1nc(Cl)[nH]c(NCCc2ccsc2)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCCc2ccsc2)c1F)OC1CCCCO1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-Chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4(1H)-pyrimidinone hydrazone as a brown sticky solid (0.1401 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.253 g, 0.586 mmol) were dissolved in DMF (7 mL). NMM (0.27 mL, 2.90 mmol) was added, followed by HOAt (0.080 g, 0.588 mmol) and EDC (0.112 g, 0.584 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as an orange solid (0.1677 g). LCMS: (M+H)+=569.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:18]=[CH:17]2.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C.O>[CH2:23]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: Clc1ncnc2ccc(Br)cc12
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Brc1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 83.4 %

Procedure:
Prepared according to Procedure A from 6-bromo4-chloroquinazoline (5.0 g) and 5-amino-1-benzyl-1H-indazole (5.0 g) in acetonitrile (100 ml) at 100° C. The resulting precipitate was treated with triethylamine in ethyl acetate and water to give the title compound as a yellow solid, (7.37 g); δH [2H6]-DMSO 9.93(1H,s), 8.82 (1H,d), 8.52(1H,s), 8.19(1H,s), 8.09(1H,s), 7.92(1H,dd), 7.65(3H,m), 7.25(5H,m), 5.62(2H,s).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Br:40])=[C:7]([C:9](=[N:37][O:38][CH3:39])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[CH:17][CH:18]([O:20][CH3:21])[S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(OCC)C.C(OC(C)C)(C)C>O1CCCC1.CO>[CH:1]([NH:3][C:4]1[S:5][C:6]([Br:40])=[C:7]([C:9](=[N:37][O:38][CH3:39])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[CH:17][CH:18]([O:20][CH3:21])[S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CC(OC)S[C@H]12)c1nc(NC=O)sc1Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(OC)S[C@H]12)c1nc(NC=O)sc1Br
Yield: 52.1 %

Procedure:
A solution of 4-nitrobenzyl 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3-cephem-4-carboxylate (syn isomer, 2.9 g.) in a mixture of tetrahydrofuran (110 ml.) and methanol (80 ml.) was treated in a similar manner to that of Example 8-(2) (diethyl ether was used for pulverization instead of diisopropyl ether) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([NH2:45])=[O:44])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([NH2:45])=[O:44])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCNC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCNC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 26 h
Yield: 44.6 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.46 g) in tetrahydrofuran (10 ml) were added dropwise acetic acid (0.5 ml) and a 1.1 M solution (3.2 ml) of tetrabutylammonium fluoride in tetrahydrofuran at ambient temperature. The mixture was stirred at the same temperature for 26 hours. To the mixture was added ethyl acetate (100 ml) and water (100 ml). The aqueous layer was adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with brine, dried over medium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (10 g) and eluted with a mixture of acetone and dichloromethane (2:1 V/V) to give allyl (4R,5S,6S)-3-[(2S, 4S)-1-allyloxycarbonyl-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.17 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Br)c(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-methoxybenzoic acid (231 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 2-bromo-5-methoxybenzoyl chloride.
Reaction SMILES: Cl.[F:2][C:3]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:27][N:28]=[C:29]=[O:30]>C1C=CC=CC=1>[CH3:27][NH:28][C:29]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[C:12]([F:19])=[C:13]([F:18])[C:14]([F:17])=[C:15]([F:16])[C:3]=2[F:2])[CH2:7][CH2:8]1)=[O:30]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CN=C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a stirring solution of 5.3 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperdine hydrochloride in 100 ml of benzene was added 2.37 ml of triethylamine followed by 1.00 ml of methyl isocyanate. The reaction mixture was stirred at ambient temperature for three hours and then evaporated to a semi-solid. The semi-solid was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to afford 5.14 g (93.3%) of 1-[(N-methylamino)carbonyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 107°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]3[CH2:46][CH2:45][N:44]([CH:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:49][CH2:48]3)=[O:22])[CH:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)c(C)c1
Reaction time: 1.5 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (74 mg, 0.21 mmol) is dissolved in THF (4 mL) and CDI (68 mg, 0.42 mmol) added. The resulting solution was stirred for 90 min prior to the addition of 1-(1-methylpiperidin-4-yl)piperazine (77 mg, 0.42 mmol). The reaction was stirred at ambient temperature for 18 h, concentrated in vacuo and a portion of the resulting crude product purified using prep method B to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[CH:10]([CH3:11])[CH2:9][CH2:8][O:7][C:6]=12.C([B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([B:22]3[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]3)=[C:6]3[O:7][CH2:8][CH2:9][CH:10]([CH3:11])[N:5]3[N:4]=2)=[CH:13][CH:14]=1
Reactant: CC1CCOc2c(Br)c(-c3ccc(F)cc3)nn21
Reactant: CC(C)B1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: CC1CCOc2c(B3OC(C)(C)C(C)(C)O3)c(-c3ccc(F)cc3)nn21
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a solution of 3-bromo-2-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.5 g, 4.82 mmol, 1 eq) in THF (40 ml) is added a solution of n-Buli (3.314 ml, 1.6 M, 5.30 mmol, 1.1 eq) dropwise at −78° C. After 20 min of stirring, a solution of 1.23 g of 2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.23 mmol, 1.1 eq) in THF is added dropwise and the reaction mixture is stirred for 2 hours at −78° C. Then the reaction mixture is quenched by the addition of an aqueous solution of NH4Cl and is extracted with EtOAc. The combined organic phases are washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude is purified by silica gel chromatography (eluent cyclohexane/ethyl acetate). 760 mg (42%) of 2-(4-fluorophenyl)-7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][N:14]=[N+]=[N-])=[C:4]([O:17][CH2:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[N:3]=1.CP(C)C>O1CCOCC1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][NH2:14])=[C:4]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])=[CH:31][CH:32]=2)[N:3]=1
Reactant: [N-]=[N+]=NCCCn1cnc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc21
Agent: CP(C)C
Solvent: O
Solvent: C1COCCO1
Product: NCCCn1cnc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Azide 23 (Example 10, 100 mg, 0.23 mmol) is dissolved in 0.9 mL of 1,4-dioxane/H2O (8:1), and 0.3 mL of a trimethylphospine solution (1 M in THF) is added. The reaction is stirred at room temperature for 3 h, then all volatiles are removed in vacuo. The crude product is purified by flash column chromatography with dichloromethane/methanol (95:5 to 10:1). Yield: 87 mg (0.021 mmol, 91%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC(F)(F)F)N1CCN(C2CCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a yellow solid (73%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16]C)=[O:15])#[N:2].O[Li].O>C1COCC1.CCOCC.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: [Li]O
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Yield: 81.7 %

Procedure:
Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (3.3 g, 14.0 mmol) and LiOH—H2O (5.89 g, 140 mmol) were stirred together in THF (25 mL) and water (25 mL) at ambient temperature for 1 hour. The reaction was diluted with ether and water, and filtered to remove undissolved solids. The filtrate was collected and the aqueous layer was washed with additional ether. The aqueous layer was acidified to pH 1-2 and the resulting solid was collected. The solid was then dissolved in ethyl acetate, dried, filtered and concentrated to provide the desired product (2.53 g, 81%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=O)=[CH:4][CH:3]=1.[NH:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH2:21]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:21][NH:20][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cn1nnc2ccc(C(=O)c3ccc(Cl)cc3)cc21
Solvent: CCO
Product: Cn1nnc2ccc(C(=NNC(=O)OC(C)(C)C)c3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 59.1 %

Procedure:
A mixture of 27.17 g of (4-chlorophenyl)(1-methyl-1H-benzotriazole-6-yl)methanone, 14.24 g of 1,1-dimethylethyl hydrazinecarboxylate and 80 ml of ethanol was stirred for 21 hours at reflux temperature. The reaction mixture was cooled to room temperature and stirring was continued for 2 hours. The precipitate was filtered off, washed with ethanol and dried in vacuo at 50° C., yielding 22.8 g (59.2%) of 1,1-dimethylethyl [(4-chlorophenyl)(1 -methyl-1H-benzotriazol-6-yl)-methylene]hydrazine carboxylate (interm. 1-b).
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1.[N:13]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:20])[CH2:14]2.O>CCCCC.CCOCC.ClCCl>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[C:15]1([OH:20])[CH:16]2[CH2:19][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: O=C1CN2CCC1C2
Reactant: Ic1cnccn1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: OC1(c2cnccn2)CN2CCC1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.6 %

Procedure:
t-Butyllithium (10.6 ml of a 1.7M solution in pentane, 18 mmol) was added dropwise to a rapidly stirred solution of 2-iodopyrazine (1.86 g, 9.0 mmol) in ether (50 ml), at -45° C. After 0.25 h a solution of 1-azabicyclo[2.2.1]heptan-3-one (1 g, 9.0 mmol) in ether (20 ml) was added dropwise and the reaction mixture warmed to room temperature and stirred for 16 h. Water (25 ml) was added and the solution stirred for 0.25 h before adding dichloromethane (150 ml) and extracting. The aqueous was extracted twice more with dichloromethane (2×150 ml). the extracts combined, dried (Na2SO4.MgSO4) and the solvent removed under vacuum. The residue was purified by chromatography through alumina, eluting with dichloromethane/methanol (93:7). Recrystallisation from ethyl acetate gave 3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (0.51 g) as a pale yellow solid, m.p. 180°-183° C.; (Found C, 62.10; H,6.79; N,21.48. C10H13N3O.O.15 H2O requires C,61.95; H,6.87; N,21.68%; δ (360 MHz,CDCl3) 1.40-1.59(1H,m,CH of CH2); 2.33-2.36(1H,m,CH of CH2); 2.47(1H,dd,J=4 and 10 Hz, CH of CH2 --N); 2.59(1H,dd J=4 and 10 Hz, CH of CH2 --N); 2.74(1H,d, J=4Hz, CH-bridgehead); 2.76-2.81(1H,m,CH of CH2 --N); 2.93-3.03(2H,m,2×CH of 2×CH2 --N): 3.39(1H,dd J=1.5 and 15Hz, CH of CH2 --N); 4.10-4.30(1H,m,OH); 8.49-8.50(2H,m,pyrazine-H); 8.87(1H,m,pyrazine-H).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]2[CH:25]=[C:24]([C:26]3[C:27]([CH3:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:23]=[CH:22][C:21]=2[Cl:34])(=[O:19])=[O:18])[CH2:12][CH2:11]1)(C)(C)C>O1CCOCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]2[CH:25]=[C:24]([C:26]3[C:27]([CH3:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:23]=[CH:22][C:21]=2[Cl:34])(=[O:19])=[O:18])[CH2:12][CH2:11]1
Reactant: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)NC2CCC(CNC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)NC2CCC(CN)CC2)c1

Procedure:
4M HCl in dioxane (1.2 ml) is added to a stirred solution of {4-[5-(2-amino-4-methyl-pyrimidin-5-yl)-2-chloro-benzenesulfonylamino]-cyclohexylmethyl}-carbamic acid tert-butyl ester (Example 3-17) (0.25 g, 0.49 mmol) in dioxane (1 ml). After 18 h the solvent is removed to give the title compound.