Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[C:17]([CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[S:38][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[N:36][CH:35]=3)[CH2:29][CH2:28]2)=[C:16]1[C:45]([O:47][CH3:48])=[O:46])=O)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[C:17]([CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[S:38][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[N:36][CH:35]=3)[CH2:29][CH2:28]2)=[C:16]1[C:45]([O:47][CH3:48])=[O:46]
Reactant: COC(=O)c1c(CC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(=O)c2ccccc2n1CCCNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(CC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(=O)c2ccccc2n1CCCN
Yield: 16.9 %

Procedure:
A solution of the compound prepared in Example 330 (37 mg) in acetonitrile (1 mL) was treated with iodotrimethylsilane (0.015 mL) for 30 minutes at room temperature. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by preparative thin layer chromatography (eluant: 20% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (5 mg) with the following physical properties.
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH:3]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:28]2)=[CH:22][CH:21]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=[CH:11][CH:12]=1)=[O:5]>C(O)C.[Pd]>[CH3:40][CH:2]([CH3:1])[CH:3]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:28]2)=[CH:22][CH:21]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)C)c1

Procedure:
130 mg (0.24 mmol) of ethyl (2E)-3-{3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]phenyl}prop-2-enoate (Example 135A) were dissolved in 10 ml of ethanol, and 10 mg of palladium on carbon (10%) were added. Under an atmosphere of hydrogen, the mixture was hydrogenated at atmospheric pressure overnight. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. This gave 118 mg (0.22 mmol, 90% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH:14]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>CN(C1C=CN=CC=1)C.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:18][CH2:19][CH:20]([O:23][C:30](=[O:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21][CH2:22]3)[CH:14]=[C:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(OC(=O)CCC(=O)O)CC3)n2)cc1Cl
Temperature: 30 °C

Procedure:
A mixture of compound 1-[2-(3-chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-yl]-piperidin-4-ol (1.0 g, 2.4 mmol), 4-(N,N-dimethyl)aminopyridine (0.45 g, 3.66 mmol) and succinic anhydride (0.73 g, 7.33 mmol) in dichloroethane (20 mL) was stirred at refluxing temperature for 48 hours. The mixture was cooled to temperature in the range of 20-40° C. and solvent was removed under reduced pressure. The residue was treated with water (20 mL) and the solid precipitated was filtered and washed with isopropanol to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:20][CH2:21][C:22]#[N:23])[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.S(C)C.CO>C1COCC1>[NH2:23][CH2:22][CH2:21][O:20][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(CCC(OCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CN(CCC(OCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C

Procedure:
A solution of tert-butyl 3-(3-chlorophenyl)-3-(cyanomethoxy)propyl(methyl)carbamate (3 g, 8.9 mmol) in THF (50 mL) was heated to reflux and BH3.Me2S was added drop wise. The reaction mixture was heated to reflux overnight. MeOH was added to the mixture at −15° C. The solution was removed in vacuo to give the crude product, which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])=[O:28])=[CH:25][N:24]=1
Reactant: Cc1cccnc1CN(CCCN)C(C)c1ccccn1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(CCCNC(=O)c1ccc(O)nc1)C(C)c1ccccn1
Yield: 37.6 %

Procedure:
Using General Procedure G: To a solution of N-(3-Methyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-propane-1,3-diamine (0.33 g, 1.16 mmol) in dry DMF (3 mL) was added 6-hydroxy-nicotinic acid (0.174 g, 1.24 mmol) followed by EDCI (0.257 g, 1.34 mmol), HOBT (0.183 g, 1.35 mmol), and DIPEA (0.40 mL, 2.30 mmol). Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 177 mg (38%) of the free base of the title compound as a colorless oil. Conversion to the HBr salt gave COMPOUND 241 (270 mg, 83%) as a white solid. 1H NMR (D2O) δ 1.55 (d, 3H, J=6.6 Hz), 1.67 (quintet; 2H, J=7.2 Hz), 2.43 (s, 3H), 2.48-2.58 (m, 1H), 2.63-2.74 (m, 1H), 3.12-3.31 (m, 2H), 4.28 (s, 2H), 456 (q, 1H, J=6.6 Hz), 6.61 (d, 1H, J=9.3 Hz), 7.78-7.83 (m, 2H), 7.89-7.94 (m, 2H), 8.11 (d, 1H, J=8.1 Hz), 8.30 (d, 1H, J=8.1 Hz), 8.49-8.58 (m, 2H), 8.74 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 15.07, 16.98, 26.37, 37.59, 50.21, 50.95, 59.83, 115.31, 119.32, 125.82, 126.75, 126.83, 137.21, 137.53, 138.40, 140.83, 142.09, 148.06, 148.24, 152.11, 156.20, 165.43, 166.77; ES-MS m/z 406 (M+H). Anal. Calcd. for C23H27N5O2.3.3HBr.4.2H2O: C, 36.92; H, 5.21; N, 9.36; Br, 35.24. Found: C, 36.85; H, 5.39; N, 9.04; Br, 35.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[N:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)/C=C/c1ccn(-c2ccc(OC)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccn(-c2ccc(OC)cc2)n1
Yield: 88.7 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(methoxycarbonyl) ethenyl]-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) carboxyamide (35 mg, 0.065 mmol) in 20 mL of absolute ethanol at ambient temperature was added 10% palladium on carbon catalyst (3.5 mg). This mixture was stirred under 1 atm of hydrogen gas for 3 h and then was filtered through a pad of celite and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 15 mg (42%) of the title compound as a white powder. LRMS (ES+): 534.9 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:12]1)#[N:9].Cl.[CH3:47][CH:48]([NH2:53])[C:49]([F:52])([F:51])[F:50]>>[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:53][CH:48]([CH3:47])[C:49]([F:52])([F:51])[F:50])=[O:21])=[CH:17][CH:16]=2)[CH2:12]1)#[N:9]
Reactant: CC(N)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1)C(F)(F)F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 19, Step 3 started from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}benzoic acid and 1-methyl-2,2,2-trifluoroethylamine hydrochloride (SynQuest Labs: Cat. #93130-7-08). LCMS (M+H)+: m/z=495.2.
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:14])[CH:3]=1.[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=O.N12CCN(CC1)CC2>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:4]1[CH:3]=[C:2]2[C:12]([CH:18]=[C:16]([C:15]([OH:20])=[O:19])[NH:1]2)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(I)c(N)cc1Cl
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 129 %

Procedure:
A solution of ethyl 4-amino-2-chloro-5-iodobenzoate (1.82 g, 5.59 mmol) in N,N-dimethylformamide (18 ml) under argon was admixed with pyruvic acid (1.27 ml, 18.2 mmol) and 1,4-diazabicyclo[2.2.2]octane, evacuated and flooded with argon. Then argon was passed through the solution for 5 min, and then palladium(II) acetate (68 mg, 0.30 nmol) was added and the mixture was heated to 100° C. for 2 h. The cooled solution was filtered through Celite and the filtercake was rinsed with ethyl acetate (100 ml). The filtrate (suspension) was washed with hydrochloric acid (2 M; 2×25 ml) and with water (2×25 ml), dried over sodium sulphate and filtered. The filtrate was concentrated to dryness under reduced pressure and gives a red-brown solid (1.93 g, approx. 51% product), which was used for the next step without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][S:14]([CH2:17][CH2:18][C:19]([OH:21])=O)(=[O:16])=[O:15].S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:44]([N:51]1[CH2:55][C@@H:54]([F:56])[C@H:53]([NH2:57])[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH2:44]([N:51]1[CH2:55][C@@H:54]([F:56])[C@H:53]([NH:57][C:19](=[O:21])[CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Reactant: CS(=O)(=O)CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CS(=O)(=O)CCC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A suspension of 1,1′-carbonyldiimidazole (73.0 g, 441 mmol, 1.1 eq) in acetonitrile (3.3 L) was stirred at 20° C. until a clear solution was obtained. 3-(methylsulfonyl)propanoic acid (67.0 g, 440 mmol, 1.1 eq) was then added and the mixture was stirred at 25° C. for 3 hr. (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate (220 g, 400 mmol, 1.0 eq) was added and the mixture was stirred at 25° C. for 16 hr resulting in a fine white slurry. The solids were filtered off and the byproduct cake washed with acetonitrile (600 mL). The acetonitrile solution was then concentrated to a low stir volume and then taken up in EtOAc (2.0 L) and washed with 1 N aqueous sodium bicarbonate (1.3 L). The aqueous layer was back extracted with EtOAc (500 mL) and the combined EtOAc layers were washed with water (1.0 L). The resulting EtOAc solution was distilled to remove about 2.0 L of distillate and then displaced with 2-propanol under atmospheric conditions until the internal temperature rose to 78° C. while maintaining a total volume of 2 L. The batch was then cooled to 20° C. and granulated at 20° C. for 12 hr resulting in product crystallization. The desired product was isolated by filtration and the cake washed with 2-propanol (600 mL), then dried in an oven at 40° C. under reduced pressure for 12 hr. The title compound (108 g, 308 mmol) was isolated in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br. d., J=7.0 Hz, 1 H) 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 4.90 (ddt, J=53.4, 5.3, 2×1.7 Hz, 1 H) 4.25 (dddd, J=26.4, 13.9, 7.0, 1.4 Hz, 1 H) 3.61 (d, J=13.2 Hz, 1 H) 3.57 (d, J=13.2 Hz, 1 H) 3.36-3.28 (m, 2 H) 3.03 (dd, J=9.3, 7.5 Hz, 1 H) 2.97 (s, 3 H) 2.80 (dd, J=24.0, 11.6 Hz, 1 H) 2.66 (ddd, J=30.6, 11.6, 5.3 Hz, 1 H) 2.57 (td, 2×7.7, 1.4 Hz, 2 H) 2.18 (dd, J=9.4, 6.7 Hz, 1 H). m/z (EI+) for C15H21FN2O3S 329.7 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:11][C:10]=2[F:29])[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CCCCO>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][C:9]=1[O:8][C:4]1[CH:3]=[C:2]([NH:31][CH3:30])[N:7]=[CH:6][N:5]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCCCO
Product: CNc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ncn1
Yield: 34 %

Procedure:
A solution of N1-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (100 mg, 0.42 mmol, Example 4) in n-BuOH (3 mL) was treated with 2 M methylamine/THF (0.2 mL) and heated in a screw cap vial at 80° C. for 12 h. The mixture was concentrated and the residue purified by preparative HPLC using a gradient of MeOH—H2O containing 0.1% TFA. The fraction containing the product was lyophilized to give the title compound as a pale yellow solid (60 mg, 34%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.36 (br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, J=12.1 Hz), 7.64-7.62 (m, 2H), 7.36-7.27 (m, 2H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 5.95 (br s, 1H), 3.49 (s, 2H), 2.80 (s, 3H); MS(ESI+) m/z 414.16 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13]([O:12][C:11]3[CH:10]=[CH:9][C:8]([CH:16]([N:18]([OH:19])[C:25]([NH2:24])=[O:26])[CH3:17])=[CH:7][C:6]=3[S:5]2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc2c(c1)Sc1cc(Cl)ccc1O2)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step 1 (320 mg, 1.09 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (295 mg, 2.18 mmol) and the mixture was stirred at room temperature for 45 minutes. After addition of water (5 mL) the mixture was stirred a further 10 minutes, then the THF was evaporated, the residual aqueous suspension diluted with water and filtered to afford the title compound as a white solid, m.p.: dec 173° C. (gassing).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.N([O-])=O.[Na+].[C-:17]#[N:18].[K+]>F[B-](F)(F)F.[H+].O>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2)#[N:18]
Reactant: CC1Cc2cc(N)ccc2C1=O
Reactant: [C-]#N
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: CC1Cc2cc(C#N)ccc2C1=O
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
A solution of 5-amino-2-methyl-1-indanone (10.0 g) in fluoroboric acid (40%;28.0 ml ) was treated at 0°-5° with sodium nitrite (4.7 g) in water (8.0 ml ). The diazonium salt solution was added to cuprous cyanide (25.0 g) in potassium cyanide (37.5 g) in water (100 ml ) at 40°. The mixture was stirred at 10° for 10 minutes, cooled and extracted with chloroform. The extract was evaporated and the residue recrystallised from aqueous ethanol to give 5-cyano-2-methyl-1-indanone(7.89 g; m.p. 90°-1°) which was converted into 7-cyano-4,4a-dihydro-[5H]-indeno[1,2-c]pyridazin-3[2H]-one by the procedures given in method A (iii, iv).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:28][C:29]([O:31]C)=[O:30])[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH2:26][CH3:27])[C:18]4[C:23]([C:24]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:28][C:29]([OH:31])=[O:30])[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH2:26][CH3:27])[C:18]4[C:23]([C:24]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)OC)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
512 mg methyl [(3,5-dichloro-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 5 ml of tetrahydrofuran. 3 ml 1 N sodium hydroxide solution are added and the mixture is stirred for 3 hours at ambient temperature. It is diluted with ice water and the precipitated solid is suction filtered. The solid is taken up in 15 ml dichloromethane and the organic phase is dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on silica gel with dichloromethane/methanol (10:0 to 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:9][O-:10].[Na+].C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:10][CH3:9])[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)ccn1

Procedure:
4-Bromo-2-chloropyridine, sodium methoxide (1.6 equiv.) and toluene (6.1 volumes) were heated to 95° C. for 40 h. Toluene (6.1 volumes) and water (3 volumes) were added and the lower aqueous phase cut away. The organic was washed with water (1.5 volumes) and then the volatiles evaporated to give the title compound as an oil. HRMS (ES, M+H) Calcd 187.9711. Found 187.9711.
Reaction SMILES: Br[C:2]1SC2C=C(OC)C=CC=2[N:6]=1.ClC1C=C(B(O)O)C=NC=1OC.Br[C:26]1[N:31]=[CH:30][C:29]([C:32]2[S:33][C:34]3[CH:40]=[C:39](OC)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][CH:27]=1>>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:29]1[CH:28]=[CH:27][C:26]([NH:6][CH3:2])=[N:31][CH:30]=1
Reactant: COc1ccc2nc(Br)sc2c1
Reactant: COc1ccc2nc(-c3ccc(Br)nc3)sc2c1
Agent: COc1ncc(B(O)O)cc1Cl
Product: CNc1ccc(-c2nc3ccccc3s2)cn1

Procedure:
2-Bromo-6-methoxy-1,3-benzothiazole (49 mg, 0.20 mmol) and (5-chloro-6-methoxypyridin-3-yl)boronic acid (45 mg, 0.24 mmol) were reacted according to the procedure used for the preparation of 2-(6-bromopyridin-3-yl)-6-methoxy-1,3-benzothiazole to give the title compound (0.2 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.51 (d, 1 H) 8.03 (dd, 1 H) 7.87 (d, 1 H) 7.43 (d, 1 H) 7.10 (dd, 1 H) 4.08 (s, 3 H) 3.88 (s, 3 H); MS m/z (M+H) 291.
Reaction SMILES: [CH:1]([C:3](C)([CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5][C:6]([O:8]C)=[O:7])=O.O=O>>[CH3:1][C:3]1([CH2:10][CH2:11][CH3:12])[O:8][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: CCCC(C)(C=O)CCC(=O)OC
Agent: O=O
Product: CCCC1(C)CCC(=O)O1
Yield: 61 %

Procedure:
Using a method similar to Example 1, 186 parts of methyl 4-formyl-4-methyl-heptanoate are reacted with 80 parts of oxygen in the course of 5 hours. 86 parts (61% of theory) of γ-methyl-γ-propyl-γ-butyrolactone (boiling point 117°-119° C./20 mbar) are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[ClH:17].[NH4+:18].[Cl-]>C(Cl)Cl.CO>[ClH:17].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:18])=[NH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: N#CCCCOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: N=C(N)CCCOCc1ccccc1
Reaction time: 144 h

Procedure:
A solution of 4-benzyloxybutyronitrile (16.5 g.) and EtOH (8.6 g.) in CH2Cl2 (100 ml.) was saturated with HCl gas at 0° and the mixture kept at 0° for 6 days. The resulting suspension was evaporated to dryness in vacuo and the residue was slurried with dry ether. The insoluble solid was added to 40% aqueous K2CO3 (120 g.) at 0° and the oil which separated was extracted with CH2Cl2 (2×100 ml.). The CH2Cl2 layer was washed with a little water, brine and then dried to give the crude imidate (14 g.). This was stirred with NH4Cl (3.5 g.) in MeOH (100 ml.) for 24 hours and the solution was evaporated to give a crude sample (14.6 g.) of 4-benzyloxybutanamidine hydrochloride.
Reaction SMILES: C(OC(N[C@H](C([NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15]C1ON=C(Br)C1)=O)C)=O)(C)(C)C.[C:25]([C:29]([OH:31])=[O:30])([F:28])([F:27])[F:26].C(Cl)Cl>>[F:26][C:25]([F:28])([F:27])[C:29]([OH:31])=[O:30].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH3:15]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC(Br)=NO1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)O

Procedure:
N-tert-butoxycarbonyl-L-alanyl-beta-(3-bromo-4,5-dihydroisoxazol-5-yl) alanine, 0.8 gm, was taken in 50 ml of 20% CF3CO2H/CH2Cl2 at room temperature for 2 hours. Concentration gave a residue which was purified by HPLC, (reverse phase, eluting with water), to give two isomers as fluffy white material after lyophilization. 1H NMR (80 MHz, D2O): delta 1.55 (d, 3H, J=7.5 Hz, CH3), 2.0-2.4 (m, 2H, CH2), 2.9-3.7 (ABX, 2H, CH2CHO), 4.1 (q, 2H, J=7.3 Hz, OCH2), 4.4-5.0 ppm (m, CHN, CHO, plus HOD solvent peak). Most polar set of isomers from the HPLC: 13C NMR (20 MHz, D20): delta 173.2, 173.1 (CO), 143.5 143.4 (BrC=N), 82.7, 81.8 (CHO), 51.8, 50.5 (broad, CHN), 49.0, 48.9 (CH2), 38.6 (CH2), 19.2 ppm (CH3). Least polar isomer: 13C NMR (20 MHz, D20): delta 180.2, 173.0 (CO), 143.5, 143.4 (BrCN), 83.6, 82.4 (CHO), 55.9, 54.9 (broad, CHN), 52.0 (CHN), 49.1, 48.7 (CH2), 39.3, 38.9 (CH2), 19.4 (CH3).
Reaction SMILES: CNCC[C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1.[Br:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=1>>[Br:11][C:12]1[N:17]=[C:16]([C:18]([N:8]([CH3:10])[CH2:9][CH2:5][C:6]2[CH:5]=[CH:9][N:8]([CH3:10])[N:7]=2)=[O:20])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CNCCc1cnn(C)c1
Product: CN(CCc1ccn(C)n1)C(=O)c1cccc(Br)n1

Procedure:
The title compound was prepared as described in Example 283, Step 1 using N-methyl-2-(1-methyl-1H-pyrazol-4-yl)ethanamine (125 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.C=O.[CH:13](O)=O>O>[CH3:13][N:3]1[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[NH:6][C:2]1([CH3:10])[CH3:1]
Reactant: O=CO
Reactant: CC1(C)NC(=O)C(C)(C)N1
Agent: C=O
Solvent: O
Product: CN1C(C)(C)NC(=O)C1(C)C
Temperature: 30 °C

Procedure:
A 500 ml. resin kettle, equipped with a mechanical stirrer, reflux condenser, thermometer in thermowell, and an addition funnel, was charged with 122.9 g. (0.8642 moles) of 2,2,5,5-tetramethylimidazolidin-4-one, 74.8 g. (0.8642 moles) of 37% formalin solution, and 200 ml. of water. This mixture was stirred without heating as 44.2 g. (0.8642 moles) of 90% formic acid was added over the course of 20 minutes, with the mixture warming up to 30° C. and becoming a solution in this time.