Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=[C:9]([O:19][CH2:20][O:21][CH3:22])[C:8]=1[O:23][CH3:24].CN(C)CCN(C)C.C([Li])CCC.I[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[C:49]([O:50][CH2:51][O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=[C:46]([O:56][CH2:57][O:58][CH3:59])[C:45]=1[O:60][CH3:61]>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[CH3:61][O:60][C:45]1[C:46]([O:56][CH2:57][O:58][CH3:59])=[CH:47][C:48]([O:54][CH3:55])=[C:49]([O:50][CH2:51][O:52][CH3:53])[C:44]=1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:10]1[C:9]([O:19][CH2:20][O:21][CH3:22])=[C:8]([O:23][CH3:24])[C:7]([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])=[C:12]([O:13][CH2:14][O:15][CH3:16])[C:11]=1[O:17][CH3:18]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCI)c1OC
Reactant: COCOCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
1.0 Gram of 1-methoxymethoxy-2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethane was dissolved in a mixed solvent of 20 ml of toluene with 5 ml of hexamethylphosphoric triamide, to this solution was added 0.52 ml of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C. in a dry ice-acetone bath, then 2.7 ml of n-butyllithium (1.6 mole solution) was added dropwise to the reaction mixture. 15 Minutes later, a solution prepared by dissolving 1.56 g of 1-(5-iodopent-1-yl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene in 12 ml of toluene was added to the reaction mixture, and the temperature of the reaction mixture was gradually elevated to room temperature and the reaction mixture was stirred further for 4 hours. 50 Milliliters of diethyl ether was added to the reaction mixture, and the organic layer was washed with water, and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate. After concentration, the residue thus obtained was purified by means of a silica gel column chromatography (diameter 3 cm×length 10 cm, Merck, eluent: 30% ethyl acetate-n-hexane) to obtain 2.1 g of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(2-methoxymethyloxyethyl)phenyl]pentane. Amorphous powdery substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:6].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1ccc(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of tert-butyl (2S)-2-(3-fluoro-4-methylbenzoyl)pyrrolidine-1-carboxylate (1.35 g, 4.38 mmol), which had been obtained in Example 1 (1a), in methanol (5 mL), sodium borohydride (0.20 g, 5.23 mmol) was added under ice cooling, and stirred at room temperature for 0.5 hours. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound as an orange oily substance (1.30 g, yield 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([N:6]1[CH2:5][CH2:4][NH:3][C:2]([CH3:8])([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN(S(C)(=O)=O)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 2,2-dimethylpiperazine (400 mg) and triethylamine (0.59 mL) in dichloromethane (10 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (10 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to afford 1-methanesulfonyl-3,3-dimethyl-piperazine as a white solid (412 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[OH:38]/[N:37]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-tert-butyl 3-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)azetidine-1-carboxylate and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=486.3 ([M+H]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccccc21
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, a solution of indole (15.0 g, 128 mmol) in dry acetonitrile (300 mL, 0.4 M) was treated with sodium hydride (95%, 3.69 g, 153 mmol) and stirred for 30 min. Ethyl bromoacetate (17.0 mL, 153 mmol) was added in a dropwise manner over 10 min and the solution was stirred at room temperature for 16 h. After concentrating under reduced pressure, the resulting residue was dissolved in ethyl acetate and washed with sat'd. aq. NaCl. The organic extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (50% ethyl acetate in heptane): Rf0.25 (40% ethyl acetate in heptane) 1H NMR (DMSO-d6, 300 MHz) δ 7.53 (d, J=6.3 Hz, 1H), 7.38-7.31 (m, 2H), 7.11 (br t, J=7.2 Hz, 1H), 7.02 (br t, J=7.2 Hz, 1H), 6.45-6.43 (m, 1H), 5.10 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:23])=[O:22]
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1c(F)cccc1F
Yield: 55 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (140 mg, 0.86 mmol), 2,6-difluorobenzenesulfonyl chloride (220 mg, 1.04 mmol) and DMAP (cat.) gave the title compound (160 mg, 55%) after purification by column chromatography with DCM as the eluent followed by recrystallisation with DCM/n-pentane.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:37])([F:36])[C:29]1[C:33]([CH:34]=[O:35])=[CH:32][NH:31][N:30]=1.Cl>CN(C=O)C.O>[CH:34]([C:33]1[C:29]([C:28]([F:37])([F:27])[F:36])=[N:30][N:31]([CH2:2][C:3]([NH:5][C:6]2[S:10][C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[C:7]=2[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4])[CH:32]=1)=[O:35]
Reactant: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 49 %

Procedure:
2-(2-Bromoacetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.91 g, 8.06 mmol) was dissolved in DMF (25 mL) and potassium carbonate (2.23 g, 16.11 mmol), followed by 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (1.39 g, 8.46 mmol), added. The mixture was stirred at 60° C. for 25 min after which time the reaction mixture was diluted with water (˜800 mL), then acidified with 5 N HCl until pH 1. During acidification a free flowing solid was obtained which was collected by filtration. NMR analysis indicated ˜60-70% purity of desired product. The solid was successfully triturated with a mixture of DCM/ether to give a light beige solid which was collected by filtration. The mother liquor was concentrated and a second batch obtained using a similar process. The batches were combined to yield the title product (1.76 g, 3.95 mmol, 49%).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]([CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=2)[CH2:21]1)[CH3:19])C1C=CC=CC=1>[Pd].CO>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]([CH3:19])[CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=2)[CH2:21]1
Reactant: CN(C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1)C1CCc2cc(F)ccc2C1
Agent: [Pd]
Solvent: CO
Product: CN(C[C@@H]1CCCC[C@H]1N)C1CCc2cc(F)ccc2C1
Reaction time: 3.5 h

Procedure:
A mixture of benzyl((1R,2S)-2-{[((2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino]methyl}cyclohexyl)carbamate (280 mg, 0.66 mmol), methanol (20 mL) and 10% palladium on charcoal (56 mg) was shaken under a hydrogen atmosphere (55 psig) for 3.5 hours. The mixture was filtered, the solids were washed with methanol and the filtrate was concentrated under vacuum. The residue (110 mg, 57%) was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)[CH:10]=2)=[CH:6][N:5]=[C:4]([N+:21]([O-])=O)[CH:3]=1>CO.C1COCC1.[Pd]>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)[CH:10]=2)=[CH:6][N:5]=[C:4]([NH2:21])[CH:3]=1
Reactant: Cc1cn(-c2cc(Oc3cnc([N+](=O)[O-])cc3C)ccn2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2cc(Oc3cnc(N)cc3C)ccn2)cn1
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
A solution of 4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.5 g, 8.03 mmol) in MeOH (40 mL) and THF (20 mL) was treated with 10% Pd/C (50% w/w water, 0.855 g, 0.8 mmol) and hydrogenated (50 psi) for 24 h. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness. The residue was stirred with 60% EtOAc/Hex for 15 min. The suspension was collected by filtration, washed with 60% EtOAc/Hex, and dried in vacuo to afford 4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.75 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=1.3 Hz, 1H), 8.27 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.30 (d, J=2.2 Hz, 1H), 6.62 (dd, J=5.8, 2.2 Hz, 1H), 6.39 (s, 1H), 5.94 (s, 2H), 2.13 (s, 3H), 1.96 (s, 3H); MS (ESI) m/z: 282.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:21]=3)\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:36])=[O:35]
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and methanesulphonylchloride
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:18][C:19]([OH:21])=[O:20])[C:15]([OH:17])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:16][C:15](=[O:17])[C@H:14]([CH2:18][C:19]([OH:21])=[O:20])[CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Reaction time: 18 h
Yield: 99 %

Procedure:
(S)-2-((7-Bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinic acid (95 mg, 0.266 mmol) was suspended in toluene (15 mL). p-Toluenesulfonic acid monohydrate (3.5 mg, 0.018 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 18 hours. Mixture was concentrated to dryness. Title compound was obtained as tan solid in 99% yield. LCMS (M−H)−=339.0, 337.0.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([O:28]C)=[O:27])[CH2:22][C:23](=[O:25])[NH2:24])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1>[NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][C:23](=[O:25])[NH2:24])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
Same procedure as above with N-Boc-Tyr(Bn)-Asn-OMe (1.035 g, 2.072 mmol), aqueous LiOH (1 M, 2.2 mL, 2.2 mmol) in THF (15 mL). A beige solid was obtained (1.03 g, 100%) which was used in the next step without further purification. 1H NMR (300 MHz, CD3OD) δ 1.35 (s, 9H, (CH3)3), 2.73-3.13 (m, 4H, CH2), 4.29 (m, 1H, CHα), 4.72 (m, 1H, CHα), 5.06 (s, 2H, CH2 (Bn)), 6.92 (d, J=5 Hz, 2 aromatic H), 7.17 (d, J=5 Hz, 2 aromatic H), 7.33-7.44 (m, 5 aromatic H). 13C NMR (75 MHz, CD3OD) δ 28.7 ((CH3)3), 37.7, 38.3 (CH2 Tyr and Asn), 50.4 (CHα Asn), 57.5 (CHα Tyr), 71 (CH2 (Bn)), 80.7 (C(CH3)3), 116.0, 128.5, 128.8, 129.5, 130.9, 131.5, 131.8, 138.8 (11 aromatic C), 157.6, 159.2 (Car-O, CO carbamate), 174.2, 174.4, 175.0 (CO acid, CO amide).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:3][N:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH2:27][C:28](O)=[O:29])[CH:18]=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:14][C:15]1[CH:16]=[C:17]([CH2:27][C:28]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)=[CH:12][N:11]=2)=[O:29])[CH:18]=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1
Reactant: Nc1ccc(-c2ccnnc2)cn1
Reactant: Cc1cc(CC(=O)O)ccc1-c1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3ccnnc3)cn2)ccc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(pyridazin-4-yl)pyridin-2-amine 134-1 (53 mg, 0.31 mmol), 2-(3-methyl-4-(pyridazin-4-yl)phenyl)acetic acid 134-3 (73 mg, 0.32 mmol), HATU (122 mg, 0.32 mmol) and DIEA (80 uL, 0.46 mmol) in DMF (1.0 ml) was stirred at room temperature overnight. Then it was distributed between ethyl acetate (40 ml) and 3% Na2CO3 aqueous solution (40 ml) and extracted with 0.5 N HCl solution (30 ml). The aqueous extraction was treated with Na2CO3 to adjust the pH to around 10 followed by extraction with ethyl acetate (30 ml×2). The combined organic extractions were dried over Na2SO4 and concentrated by evaporation. The residue was subjected to reverse phase HPLC to yield 2-(3-methyl-4-(pyridazin-4-yl)phenyl)-N-(5-(pyridazin-4-yl)pyridin-2-yl)acetamide 134 as off white solid. MS m/z 383.2 (M+1).
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].[Cl:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>>[C:2]([O:7][CH2:8][CH2:9][NH:10][S:14]([CH2:13][CH2:12][Cl:11])(=[O:16])=[O:15])(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(=O)OCCN
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Product: C=C(C)C(=O)OCCNS(=O)(=O)CCCl

Procedure:
2-Aminoethyl methacrylate hydrochloride is condensed with 2-chloroethanesulfonyl chloride to produce the 2-(2-chloroethylsulfonylamino)ethyl methacrylate. ##STR23##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 110 °C
Yield: 10.9 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), 4-isopropoxyphenylboronic acid (68.6 mg, 0.38 mmol), and 2 N aqueous potassium carbonate solution (1.1 mL, 2.2 mmol) in toluene (1.6 mL) and EtOH (2.4 mL) was degassed with N2 and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29.4 mg, 0.036 mmol) under N2. The reaction mixture was sealed in a pressure tube and heated to 110° C. for 1 hour. The cooled reaction mixture was acidified to pH 5 and concentrated in vacuo. The resulting solid was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (13.0 mg, 11% yield). MS (ES+) 331.1 (M+H)+. Retention time=3.05 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([N:11]=[C:12]2[N:20]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[S:13]2)=[C:4]([F:22])[CH:3]=1.[OH:23][CH2:24][CH2:25][C:26]1[S:30][CH:29]=[N:28][C:27]=1[CH3:31].C(N(CC)CC)C>C(OC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])=[O:9])=[CH:6][C:5]([N:11]=[C:12]2[N:20]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[S:13]2)=[C:4]([F:22])[CH:3]=1
Reactant: Cc1ncsc1CCO
Reactant: O=C(Cl)c1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: COC(C)=O
Product: Cc1ncsc1CCOC(=O)c1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3.6 g of 9-[4-chloro-2-fluoro-5-(chlorocarbonyl)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan7-one in 10 ml of methyl acetate is added dropwise, with stirring, at room temperature to a solution of 1.2 ml of 5-(2-hydroxyethyl)-4-methylthiazole and 1.5 ml of triethylamine in 50 ml of methyl acetate. After stirring at room temperature for 12 hours, the precipitated triethylamine hydrochloride is filtered off and the filtrate is concentrated by evaporation, yielding 3.8 g of the title compound in the form of an oil with nD22 1.6030.
Reaction SMILES: CP(C)C.[CH3:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([C:11](=N)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14]C=2)=[CH:9][CH:8]=1>[Ni].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:11]1([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:20][CH:19]=2)[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=N)c2ccccc2)cc1
Agent: [Ni+2]
Agent: [Ni]
Agent: CC(=O)/C=C(/C)[O-]
Product: COc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 1600 %

Procedure:
The procedure was identical to Example 1, with the exception that the nickel catalyst used was derived in situ from a combination of anhydrous nickel acetylacetonate (0.026 g; 5 mol %) and trimethylphosphine (0.20 mL of 1M solution in toluene; 10 mol %). GC analysis of the organic phase of the hydrolyzed reaction sample after 2 h at 60° C. showed the presence of 1.76 mmol (88% yield) of 4-phenylanisole, 0.11 mmol of 4-methoxybenzophenone imine, and no remaining 4-methoxybenzonitrile in the reaction mixture.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[CH3:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[N:16][C:15]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:19]([C:17]1[S:18][C:14]([CH3:13])=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=1)(=[O:20])=[O:21])[CH3:4]
Reactant: Cc1sc(S(=O)(=O)Cl)nc1-c1ccccc1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc(-c2ccccc2)c(C)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-methyl-4-phenyl-thiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 7.68 (d, 2H), 7.51 (t, 2H), 7.44 (t, 1H), 4.05 (q, 2H), 3.26 (s, 2H), 3.10 (t, 2H), 2.64 (s, 3H), 2.63 (t, 2H), 1.16 (t, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=1[CH3:15])[CH2:2][CH3:3].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].O.[Cl-].[Na+].O>CO>[CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:8]([CH3:15])=[CH:9][C:10]([NH:14][CH2:23][C:21]2[S:22][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:11][C:12]=1[CH3:13])[CH2:2][CH3:3]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCCOC(=O)Nc1c(C)cc(N)cc1C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOC(=O)Nc1c(C)cc(NCc2ccc(Cl)s2)cc1C
Temperature: 130 °C
Yield: 49 %

Procedure:
(4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester (84 mg) and 5-chloro-thiophene-2-carbaldehyde (48 uL) were dissolved in methanol (3 mL) and heated to 130° C. for 5 minutes in a sealed microwave process vial. Sodium cyanoborohydride (95 mg) was added and the reaction mixture was heated to 130° C. for 5 minutes in a sealed microwave process vial, followed by addition of water/brine (1:1, 3 mL). The product was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with brine (5 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 66 mg (49% yield) of the title compound as an oil. LC-MS (m/z) 353 (MH+); tR=3.06, (UV, ELSD) 87%, 87%.