Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)([CH3:3])[CH3:2].[CH3:9][C:10]([NH2:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:8][CH:6]([CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[CH2:7][NH:21][C:10]([CH3:20])([CH3:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CC(C)OCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COC(C)C)cc1
Yield: 17.9 %

Procedure:
Using the method of Example 15, supra, isopropylglycidyl ether (126 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 53 mg of the title compound as a clear, colorless oil; GC/EI-MS, m/z (rel. int.) 296 (M+1, 0.2), 280 (1.4), 222 (1.5), 174 (100), 132 (12), 121(24); 1H-NMR (CDCl3) 7.03 (2H, d, J=8.4), 6.77 (2H, d, J=8.4), 3.72 (3H, s), 3.70 (1H, m), 3.53 (1H, m), 3.38 (2H, m), 2.80 (1H, broad s), 2.73 (2H, m), 2.58 (4H, m) 1.09 (6H, m), 1.01 (3H, s), 0.99 (3H, s); 13C-NMR (CDCl3) δ 157.9, 131.2, 129.9, 113.2, 73.4, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1, 13.8.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.C(=O)(O)O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1>C(O)(C)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:28]=2)=[CH:24][CH:25]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: COc1ccc(NC(=N)N)cc1
Agent: O=C(O)O
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
A mixture of 14.4 g of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one and 16.1 g of 4-methoxyphenyl guanidine carbonate in 200 ml of isopropanol was heated at reflux for 20 hours. The reaction mixture was cooled, the crude product was collected by filtration and washed with water. The material was recrystallized from isopropanol to give the desired product as light yellow crystals, mp 121°-122° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][OH:15])=[CH:13][C:8]=2[N:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]>[O-2].[Mn+4].[O-2].ClCCl>[CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[N:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nnc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCn1nnc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.2 %

Procedure:
A mixture of 36.5 parts of 1-butyl-1H-benzotriazole-5-methanol, 35 parts of manganese(IV) oxide and 390 parts of dichloromethane was stirred for 12 hours at room temperature. The manganese(IV) oxide was filtered off over diatomaceous earth and another portion of 35 parts of manganese(IV) oxide was added to the filtrate. After stirring for 12 hours at room temperature, the whole was filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using dichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 15.3 parts (42.2%) of 1-butyl-1H-benzotriazole-5-carboxaldehyde as a residue (int. 57).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[C:14]([C:19]([OH:21])=O)=[N:15][CH:16]=[CH:17][N:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[C:14]([C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[N:15][CH:16]=[CH:17][N:18]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1COCCN1
Reactant: O=C(O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: O=C(c1nccnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1)N1CCOCC1

Procedure:
This title compound was prepared following procedure described in example 42 step 3 wherein 3-(3,4-dichloro-benzenesulfonylamino)-pyrazine-2-carboxylic acid was coupled with morpholine. The crude was purified by flash column (65% ethyl acetate in hexane) to afford the above title product as a white powder. MS: (M+Na)/z=451.0.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[C:11]([C:13]2([CH:16]([F:18])[F:17])[CH2:15][CH2:14]2)[CH:10]=[C:9]([Br:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[ClH:20].[CH2:21](O)[CH3:22]>>[ClH:20].[NH2:1][C@H:2]([C:7]1[CH:12]=[C:11]([C:13]2([CH:16]([F:17])[F:18])[CH2:15][CH2:14]2)[CH:10]=[C:9]([Br:19])[CH:8]=1)[CH2:3][C:4]([O:6][CH2:21][CH3:22])=[O:5]
Reactant: CCO
Reactant: N[C@@H](CC(=O)O)c1cc(Br)cc(C2(C(F)F)CC2)c1
Agent: Cl
Product: CCOC(=O)C[C@H](N)c1cc(Br)cc(C2(C(F)F)CC2)c1

Procedure:
To a solution of (S)-3-amino-3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)propanoic acid (from step A above) (225.5 mg, 0.675 mmol) in absolute ethyl alcohol (3 mL) was added absolute ethanol saturated with anhydrous HCl gas (7 mL) and the reaction mixture was heated at reflux under nitrogen for 3 h to give a colorless solution. The solvent was evaporated in vacuo to give a colorless viscous liquid. The residue was triturated with diethyl ether (10 mL) and the solvent was evaporated in vacuo to give the desired (S)-ethyl 3-amino-3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)propanoate hydrochloride salt as a colorless foamy solid (253.0 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 362 (79BrM+H), m/z 364 (81BrM+H), m/z 384 (79BrM+Na) and m/z 386 (81BrM+Na); Calcd for C15H18BrF2NO2:362.21. The isolated solid will be used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A mixture of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea (Compound 77, example 1.61) (0.270 g, 0.69 mmol) in anhydrous 1,2-dichloroethane (10 mL) was cooled to 0° C. on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (0.368 g, 2.76 mmol) was added and the reaction mixture stirred at 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C. for 1 hour. Ethyl acetate was added and washed with potassium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product that was further purified via HPLC. The corresponding fractions were collected and lyophilized to afford Compound 120 as a white solid in 75.0% yield. LCMS m/z (%)=379 (M+H 35Cl, 100), 381 (M+H 37Cl, 40). 1H NMR (400 MHz. DMSO-d6) δ: 9.81 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 1H), 7.40-7.31 (m, 3H), 7.09-7.04 (m, 1H), 6.99 (d, J1=8.72 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O.Cl[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:28]2[C:29]([C:30]#[N:31])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: N#Cc1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(-c2ccccc2C#N)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
Under argon, 5-ethoxy-2-fluorophenylboronic acid (300 mg, 1.63 mmol), potassium phosphate (433 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol) were dissolved in abs. N,N-dimethylformamide (8 ml), and the mixture was stirred at room temperature for 5 minutes. 2-Chlorobenzonitrile (112 mg, 0.82 mmol) was then added, and the reaction mixture was stirred at 160° C. for 4 h. After cooling to room temperature, water (>100 ml) was added and the aqueous phase was repeatedly extracted thoroughly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered off and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 5′-ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 76% of theory) in the form of a colourless solid. 5′-Ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 0.62 mmol) was then dissolved in methanol (5 ml), finely powdered potassium hydroxide (174 mg, 3.10 mmol) was added and the mixture was stirred under reflux conditions for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, water was added and the resulting precipitated solid was filtered off and dried. This gave 2-ethoxyphenanthridin-6(5H)-one (72 mg, 46% of theory) as a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.58 (br. s, 1H, NH), 8.56 (d, 1H), 8.32 (d, 1H), 7.86 (d, 1H), 7.82 (dd, 1H), 7.64 (dd, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 4.17 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@H:13]1[CH2:12][NH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Yield: 101.1 %

Procedure:
A mixture of benzyl (3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidine-1-carboxylate (3.86 g, 9.59 mmol) in MeOH (50 mL) was hydrogenated in the presence of 10% Pd on carbon (0.30 g) under 25 psi of hydrogen for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the sub-title compound (2.6 g, 100%). LCMS calc. for C11H20F3N2O2(M+H)+: m/z=269.1. found: 269.2.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].[N:14]1([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:10]=[C:6]1[NH:5][C:4]2[S:11][CH:12]=[CH:13][C:3]=2[C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:16]2)=[C:7]1[C:8]#[N:9]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2ccsc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2[nH]c1=O

Procedure:
To yield a compound of structure (III) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, the intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), was reacted with piperazin-1-yl-thiophene-2-yl-methanone to yield 6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (51). The compound of formula (51) was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield the target compounds of structure (III) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, as shown in Scheme 26.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[Na+].C1(C)C=CC=CC=1.Cl>C1OCCOCCOCCOCCOC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][O:14][C:12]([CH3:15])([CH3:13])[CH3:11]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCc1c(F)cccc1Cl
Temperature: 45 °C
Yield: 89.9 %

Procedure:
A mixture of 200 g (1.117 mole) of 2-chloro-6 fluorobenzyl chloride, 118 g (1.23 mole) of sodium t-butoxide, 2.2 mL (11 mmole) of 15-crown-5 (15-C-5) and 1.2 L of toluene was heated at reflux temperature for four hours. After allowing the reaction mixture to cool to 45° C., 600 mL of water was added followed by 90 mL of 2N HCl. After separation, the organic phase was concentrated in vacuo to give a dark oil. Distillation using a 5-tray Oldershaw column, sand bath to 155° C., gave 217.5 g of 1-chloro-3-fluoro-2-[(1,1-dimethylethoxy)methyl]-benzene as a clear liquid (bp 60-64° C./0.6 mm Hg.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2
Reactant: O=c1ccc2c([N+](=O)[O-])cccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc2[nH]c(=O)ccc12
Yield: 100.3 %

Procedure:
4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(NCCCN3CCOCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-morpholinopropylamine according to general procedure 1 providing the amino compound (1.30 g, 59%) as an orange oil; Rf=0.66 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.47 (d, J=9.7 Hz, 1H), 3.71-3.69 (m, 4H), 3.42 (t, J=6.9 Hz, 2H), 2.51-2.48 (m, 6H), 1.92-1.89 (m, 2H); ES-MS: (M+H)=340, 342 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10](O)=[N:9][C:8]2=[O:14])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:10]1[N:11]=[CH:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:14])[N:9]=1
Reactant: O=c1nc(O)ncn1Cc1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A toluene solution (25 mL) of 1-(4-chlorobenzyl)-4-hydroxy-1,3,5-triazin-2(1H)-one (600 mg, 2.52 mmol) synthesized in Reference Synthesis Example 10, N,N-diisopropylethylamine (0.52 mL, 4.63 mmol), and phosphorus oxychloride (0.94 mL) was stirred at 70° C. for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and toluene was added, followed by concentrating the resultant mixture under reduced pressure again. To the obtained crude product of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one, chloroform was added and the resultant solution was used in the next reaction as the chloroform solution.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 98 %

Procedure:
To a 20 mL microwave vial containing 4-chloro-3-nitropyridine (Aldrich, 1.350 g, 8.515 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 1.922 g, 9.597 mmol), 1-butanol (13.0 mL) was added, followed by DIPEA (2.213 g, 17.12 mmol). The reaction mixture was irradiated with microwaves at 130° C. for 1 h. The reaction mixture was then allowed to cool and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow solid (2.69 g, 98%). LCMS calc. for C15H23N4O4 (M+H)+: m/z=323.2. found 323.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[C:12]3[C:16]([CH:17]=2)=[N:15][N:14](C2CCCCO2)[CH:13]=3)[CH:5]=[N:6][C:7]=1[Cl:8].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1.Cl.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:36]([CH:33]1[CH2:35][CH2:34]1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(N)c3)cc3nn(C4CCCCO4)cc23)cs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(=O)(=O)C4CC4)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
N-[6-(5-Amino-6-chloro-3-pyridinyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (40 mg) was dissolved in pyridine (1 ml) and cyclopropanesulfonyl chloride (24 mg) was added. The reaction was stirred at RT for 1 h. DMAP (3 mg) and cyclopropanesulfonyl chloride (24 mg) were added and the reaction was stirred for 1 h. Further cyclopropanesulfonyl chloride (48 mg) was added and the reaction stirred overnight. Further cyclopropanesulfonyl chloride (48 mg) was added and the reaction was stirred for 2 h. 2M HCl (aq) and DCM were added and the DCM was separated, passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:methanol (1 ml, 7:3, v/v) and purified by MDAP (method E). The product fraction was evaporated to dryness and methanol (3 ml) and a few drops of 2M HCl (aq) were added and the reaction stirred for 2 h. The reaction was evaporated to dryness to give title compound (12 mg).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]1[CH:16]=[C:17]([C:22]2([OH:32])[CH2:26][CH2:25][N:24]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:23]2)[CH:18]=[C:19](F)[CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]3)[CH:18]=[C:17]([C:22]2([OH:32])[CH2:26][CH2:25][N:24]([CH2:27][C:28]([F:29])([F:30])[F:31])[CH2:23]2)[CH:16]=1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Reactant: OC1(c2cc(F)cc(F)c2)CCN(CC(F)(F)F)C1
Product: CN1C(=O)CCc2cc(Sc3cc(F)cc(C4(O)CCN(CC(F)(F)F)C4)c3)ccc21
Yield: 30 %

Procedure:
Using an analogous procedure to that described in Example 6, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 3-(3,5-difluorophenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)pyrrolidine to give 3-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-3-hydroxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 30% yield.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH3:8][N:9]1[C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:16][C:15]2[C:10]1=[N:11][C:12]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])=[N:13][C:14]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:6][C:2]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][C:17]2[N:9]([CH3:8])[C:10]3[C:15]([N:16]=2)=[C:14]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:13]=[C:12]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[N:11]=3)[CH2:24][CH2:23]1)([CH3:7])[C:3]([NH2:5])=[O:4]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: CC(C)(Br)C(N)=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 2-bromo-2-methyl-propionamide and 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine were reacted to give 508. LCMS m/z: 532.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[N+:12]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[NH2:12]
Reactant: N#CCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: N#CCSc1ccc(N)c(N)c1
Reaction time: 2 h

Procedure:
4.1 G. of 1-amino-2-nitro-4-cyanomethylthiobenzene in 60 ml. of methanol and 12 ml. of water is treated with 1.25 g. of ferrous sulfate and 3.3 g. of iron powder at reflux. After 2 hours, 1.25 g. of ferrous sulfate and 3.3 g. of iron powder are added and heating is continued for four hours. The mixture is poured into 600 ml. of hot tetrahydrofuran and filtered. 1,2-Diamino-4-cyanomethylthiobenzene is obtained from the filtrate by evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH3:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2ncnc3ccccc23)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ncnc3ccccc23)cc1OC

Procedure:
The title compound was prepared from (3,4-dimethoxy-phenyl)-quinazolin-4-yl-amine (130 mg, 0.46 mmol), methyl iodide (0.043 ml, 0.7 mmol), sodium hydride (28 mg, 0.7 mmol, 60% oil dispersion) in DMF similar to example 21 to give 2.0 mg (2%) of white solids. 1H NMR (CDCl3): 7.88 (s, 1H), 7.55-7.45 (m, 2H), 7.31 (d, J=7.2 Hz, 1H), 6.97 (t, J=7.2 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 6.37 (d, J=2.4 Hz, J=8.1 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.53 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]([NH2:16])([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)c(F)c1
Yield: 92.5 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and isopropylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-3-fluoro-N-isopropylbenzenesulfonamide (0.40 g, 93%) was provided after purification. HRMS: calcd for C9H11BrFNO2S, 294.96779; found (EI, M+.), 294.9665. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([N:7]1[CH2:15][CH2:14][CH:10]([C:11](O)=[O:12])[CH2:9][CH2:8]1)=[O:6].C(OC(=O)C)(=O)C>>[CH:5]([N:7]1[CH2:15][CH2:14][CH:10]([C:11]([Cl:3])=[O:12])[CH2:9][CH2:8]1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=CN1CCC(C(=O)O)CC1
Solvent: CC(=O)OC(C)=O
Product: O=CN1CCC(C(=O)Cl)CC1
Reaction time: 3 h
Yield: 100 %

Procedure:
To 100 ml of freshly distilled thionyl chloride was added 30 g of N-formylisonipecotic acid at 0°. After the addition was complete, 2 ml of acetic anhydride was added and the solution was stirred at 20° for three hrs. The reaction mixture was diluted with 3 400-ml portions of petroleum ether, bp, 60°-80°. The resulting solid was collected, washed with 50 ml of ether and dried under vacuum over phosphorous pentoxide to yield 33.5 g (100%) of N-formylisonipecotic acid chloride.