Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a mixture of 4-tert-butoxycarbonylamino-benzoic acid (50 g, 0.21 mol) and HOBT (31.33 g, 0.231 mol) in dry THF (0.5 L) was added EDAC (44.44 g, 0.231 mol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (40.4 ml, 0.231 mol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (39.4 ml, 0.231 mol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (600 ml) and the resulting mixture was extracted with EtOAc (3×500 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were collected and evaporated to dryness. To the solid residue was added diethyl ether (100 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 60.5 g (77%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester as a solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Agent: OB(O)c1ccccc1
Product: COc1ccccc1-c1ccc2c(c1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 45 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-methoxyphenyl boronic acid. The title compound (85 mg) was obtained as a yellow solid, (yield=45%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1.[Li][CH2:18]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:18][C:12]1[Se:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:9][CH:8]=2)=[CH:14][CH:13]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc[se]2)cc1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1ccc(-c2ccc(OC(F)(F)F)cc2)[se]1
Temperature: -70 °C
Reaction time: 24 h

Procedure:
8.6 g (29.5 mmol) of 2-(4-trifluoromethoxyphenyl)selenophene are initially introduced in 50 ml of diethyl ether, and 25.0 ml (39.8 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −70° C. 7.4 ml (0.12 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 24 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1). The further purification is carried out by recrystallisation from n-heptane. 2-Methyl-5-(4-trifluoromethoxyphenyl)selenophene is obtained as a colourless solid (m.p. 122° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1>C(#N)C>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:7]=[C:6]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][C:3]=2[N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][CH2:21]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)c3ccccc3)cc2N)CC1
Reactant: Nc1ncc(Br)nc1C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)c3ccccc3)cc2NC(=O)c2nc(Br)cnc2N)CC1
Yield: 46 %

Procedure:
Following method 11, tert-butyl 1-(2-amino-4-benzoylphenyl)piperidin-4-ylcarbamate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (1.5 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 1-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-benzoylphenyl)piperidin-4-ylcarbamate (46%). LCMS (m/z): 595.2 (MH+); LC Rt=3.94 min.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24].C1(C)C=CC=CC=1.C([Li])CCC.[OH-].[Na+].CN(C)[CH:41]=[O:42]>CCCCCC>[CH3:22][O:21][C:4]1[C:3]([O:23][CH3:24])=[C:2]([CH:41]=[O:42])[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1c(Br)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1c(C=O)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Reaction time: 0.33 h

Procedure:
To a solution of 18.21 g. (0.0446 mole) of 9-bromo-7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 20) in 200 ml. of toluene, cooled to -78° C., is slowly added 26.0 ml. of 2.1 M n-butyl lithium in hexane. After 20 minutes at this temperature 23.1 ml. of dimethylformamide is added and the mixture is stirred for 1/2 hour. The reaction mixture, at room temperature, is poured into 10% sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine-9-carboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29]O)[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CN(C=O)C.S(Cl)([Cl:38])=O>>[Cl:38][CH2:29][CH2:28][O:27][C:26]1[C:19]2[C:20](=[N:21][CH:22]=[N:23][C:18]=2[NH:17][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[C:2]([Cl:1])[CH:3]=2)[NH:24][N:25]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1

Procedure:
2-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethanol (prepared as described in Example 1/550 mg, 1.28 mmol) was dissolved in thionyl chloride (4 ml). DMF (20 μl) was added and the mixture refluxed for 2 hours under a dry atmosphere. After evaporation of the solvent under reduced pressure, the solid residue was triturated in ether, filtered and dried under vacuum to provide the title compound as a hydrochloride salt (551 mg, 89%); NMR Spectrum: 4.03 (t, 2H), 4.58 (t, 2H), 5.28 (s, 2H), 7.18 (t, 1H), 7.29-7.34 (m, 3H), 7.45-7.53 (m, 2H), 7.83 (s, 1H), 8.32 (s, 1H), 9.25 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1C
Solvent: C1COCCO1
Product: CSCC(C)C(=S)Nc1sc(-c2cccnc2)nc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added 2-methyl-N-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)3-methylsulfanyl-propionamide (0.10 g, 0.32 mmol) in dioxane and Lawesson's reagent (0.19 g, 0.48 mmol). The vessel was capped and heated in a Biotage Initiator microwave reactor for 1 min at 130° C., with external IR-sensor temperature monitoring from the side. The reaction was concentrated to dryness and the crude material was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow semi solid (0.019 g, 18%): 1H NMR (300 MHz, CDCl3) δ 9.9 (m, 1H), 9.2 (d, 1H), 8.65 (d, 1H), 8.4 (m, 1H), 7.4 (m, 1H), 3.15 (m, 1H), 2.9 (m, 2H), 2.5 (s, 3H), 2.2 (s, 3H), 1.5 (d, 3H); ESIMS m/z 324.12 (M+1).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.O.[NH2:17][NH2:18]>CCO>[NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([NH:17][NH2:18])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-(1H-tetrazol-5-yl)benzoate (1.00 g, 4.16 mmol) in EtOH (15 mL) was added hydrazine hydrate (3.0 mL). After stirring for 15 hrs at reflux, the reaction mixture was allowed to warm up to rt. A white solid precipitated out. Filtration, washing with EtOH (2×3 mL), EtOH/water (2×3 mL) and water (2×3 mL) and drying under vacuo at 70° C. for 5 hrs gave 677 mg of the title compound as a white solid in a 80% yield.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12].CCN(C(C)C)C(C)C>CCO>[I:8][C:7]1[C:2]([NH:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: Clc1ncncc1I
Reactant: NCC(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CNc1ncncc1I
Temperature: 120 °C
Yield: 59 %

Procedure:
To a solution of 4-chloro-5-iodopyrimidine (0.250 g, 1.040 mmol) and 2,2,2-trifluoroethanamine (0.216 g, 2.184 mmol) in EtOH (volume: 2.080 ml) was added Hunig's Base (0.200 ml, 1.144 mmol). The reaction mixture was heated in a microwave for 4 hr at 120° C. and then allowed to cool to room temperature. The solvent was evaporated. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-90% EtOAc in hexanes over 25 min, tr=12 min) gave the title compound (0.188 g, 0.614 mmol, 59.1% yield) as a yellow residue. ESI MS (M+H)+=303.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.044 g, 0.11 mmol) and EtOH (3.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80° C. for 19 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 2:3) and then a gradient of methanol (2 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 20%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.67 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[CH3:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][N:19]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 21 %

Procedure:
Using 4-bromo-2-methanesulfonylaminobenzoic acid (964 mg) described in Preparation Example 225 and 1-(3,5-dimethylpyridin-2-yl)piperazine (629 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (321 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][C@H:26]2[CH2:39]OS(C)(=O)=O)=[CH:21][C:20]=1[F:45]>COCCOC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:27][C@H:26]2[CH2:39][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:1])=[CH:21][C:20]=1[F:45]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reactant: COC(=O)c1cccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cccn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Methyl 2-hydroxypyridine-3-carboxylate (1.48 g) and potassium carbonate (2.23 g) were added to a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (3.53 g) in 1,2-dimethoxyethane (70 ml). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(Cl)[Cl:15].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([Cl:15])=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 250-mL, round-bottomed flask was added 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid (2.0 g, 10 mmol, Maybridge, Cornwall, UK) and CH2Cl2 (40 mL). To the mixture was added oxalyl chloride (20 mL, 40 mmol, 2 M in CH2Cl2) and DMF (8.0 μL, 0.10 mmol). The mixture was stirred for 1.5 h at 25° C. Toluene (10 mL) was added and the mixture was concentrated to afford the title compound which was taken on to the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[N:33][CH:32]=[CH:31]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:34]1[C:35]2[C:30](=[CH:29][C:28]([NH:27][C:8](=[O:9])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:14]([CH3:15])[CH3:16])=[CH:37][CH:36]=2)[CH:31]=[CH:32][N:33]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)[Si](OCC(C(=O)O)c1ccccc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)[Si](OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To 2-phenyl-3-(triisopropylsilyloxy)propanoic acid (E400) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into NaHCO3(sat) and extracted with EtOAC. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (3-4% MeOH/CH2Cl2) gave pure N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>C(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:14](=[O:26])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 264 h
Yield: 29.5 %

Procedure:
To a stirred solution of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate (48 g, 220 mmol) in chloroform (900 mL) was added ruthenium (IV) oxide hydrate (6.0 g, 45 mmol) followed by a solution of sodium periodate (150 g, 700 mmol) in water (900 mL). The resulting heterogenous reaction mixture was stirred at room temperature for 11 days before being filtered through a short column of celite. The organic layer was removed and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with a 10% solution of sodium thiosulfate in water twice, and once with brine. This solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, 20% EA/hexanes) to give 22.5 g (64.8 mmol) of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-2-oxopiperidine-1-carboxylate (29%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.S(Cl)([Cl:13])=O>ClCCCl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: ClCCCl
Product: ClCc1cccnc1Cl

Procedure:
To 10.24 g (0.065 mole) of 2-chloronicotinic acid were added 20 ml of 1,2-dichloroethane and 9.5 ml of thionyl chloride and the mixture was refluxed for 1 hour. The reaction mixture was concentrated to give 11.9 g of 2-chloronicotinyl chloride as an orange-colored oil. When left standing at room temperature, this product solidified thoroughly.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17]([O:28][CH3:29])(=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-])=O)=[CH:20][CH:19]=1>>[CH3:29][O:28][C:17](=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Product: COC(=O)c1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)cc1
Yield: 60 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.21 mmol) was converted using mono-methyl terephthalate instead of o-toluic acid to the title compound (1.98 mg, 60%) which was obtained as a colorless liquid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:52]([C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:42](=[O:44])[CH3:43])=[CH:51][CH:50]=2)(=[O:54])=[O:53])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)cc1
Yield: 18.7 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.016 ml, 0.09 mmol) and 4-acetamidobenzenesulfonyl chloride (0.011 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (EtOAc) gave 0.006 g of a white solid. MS (ES): 643 (M+1).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.6 %

Procedure:
Under nitrogen dissolve 1-benzhydrylazetan-3-ol (5 g, 20.9 mmol), imidazole (3.5 g, 52.25 mmol) in anhydrous DMF (25 mL). Cool solution in an ice bath, add slowly tert-butyldimethylsilyl chloride (50 wt. % solution in toluene, 6.3 g, 41.8 mmol). Stir at RT for 22 h. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution. Separate organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (3.89 g, 53%).