Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.CO.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butylester (2.28 g, 4.5 mmol) are dissolved in 40 ml Dioxane/Methanol (3:1). Palladium on charcoal (10%) (170 mg, 0.16 mmol) are added under an Argon flow. The flask is evacuated and flushed three times with Hydrogen. The reaction is stirred for 6 h at room temperature. Filtration through Celite and evaporation of the solvents afforded the product: 1H NMR (DMSO, 400 MHz), ppm: 7.81 (d, 2H), 6.95 (d, 2H), 5.40 (d, 1H), 3.68 (s, 3H), 3.65 (m, 1H), 3.25 (m, 1H), 2.92 (m, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.78 (m, 2H) 1.25 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](Cl)=[N:19][N:18]=2)=[CH:9]1)(C)(C)C.[OH-:29].[Na+].Cl>C1COCC1>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:28])[CH:9]=2)=[N:18][NH:19]1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2nnc(Cl)c3ccccc23)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)Cn1cc(-c2n[nH]c(=O)c3ccccc23)c2ccccc21
Temperature: 60 °C

Procedure:
The product of step b) (50 mg, 0.13 mmol) was dissolved in 4 mL THF. NaOH (0.52 mL of 1 M aq) was added and the reaction was heated to 60° C. for 3 days. The reaction was cooled, acidified with 1 M HCl, and extracted into DCM. Concentration gave the sub-title product as a yellow oil. MS: ESI (negative): 318 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH2:13].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[C:3]2[NH:13][N:14]=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cc(Br)c2[nH]nnc2c1
Reaction time: 0.25 h

Procedure:
To a cooled (15° C.) solution of 3-bromo-5-(trifluoromethyl)benzene-1,2-diamine (1.82 g, 7.14 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite (0.517 g, 7.49 mmol) in water (10 mL). After 15 min, the product was collected by filtration and washed with 65% HOAc in water and air dried to give 1.5 g (79%) as a faint pink powder. 1H-NMR (4:1 CDCl3/CD3OD, 500 MHz) δ 8.08 (s, 1H), 7.71 (s, 1H), 4.23 (bs, 1H); 13C-NMR (4:1 CDCl3/CD3OD, 126 MHz) δ 139.9, 129.0 (q, J=33 Hz), 125.3, 123.3 (q, J=273 Hz), 113.4, 108.2. Mass spec.: 265.82 (MH)+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][N:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:22]=2)[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5]1=[O:11]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cn1cc(Br)n2cncc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)n2cncc2c1=O
Temperature: 25 °C
Yield: 18.8 %

Procedure:
A solution of compound from Example 129, step 1 (80 mg, 0.35 mmol), (3-methylsulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na2CO3 (106 mg, 1 mmol), Pd(PPh3)2Cl2 (30.0 mg) in dioxane (3 mL) and water (0.5 mL) was stirred at 120° C. for 18 h under N2. After cooling to room temperature, the mixture was filtered, concentrated and purified by prep-HPLC to give the title compound (20.0 mg, 20%). 1H NMR (Methanol-d4 400 MHz): δ 8.70-8.65 (m, 1H), 8.30-8.20 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.22 (s, 1H), 3.56 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+304.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:6][OH:7]>[Pd]>[CH3:6][O:7][C:3](=[O:4])[CH2:2][CH:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:1]1
Reactant: C1CCOC1
Reactant: CO
Agent: [Pd]
Product: COC(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 303 (490 mg, 3.1 mmol) in 1:1 THF:MeOH (10 mL) is added 10% palladium-on-carbon (74 mg), and the mixture is stirred at RT under hydrogen for 16 h. The mixture is filtered, and the filtrate is evaporated to give 481 mg of the product 304. 1H NMR (CDCl3) δ 4.0-3.9 (m, 2H), 3.70 (s, 3H), 3.40 (t, 2H), 2.25 (d, 2H), 2.01 (m, 1H), 1.65-1.60 (m, 2H), 1.40-1.25 (m, 2H); MS: m/z 159 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:10]1[CH2:9][CH:8]([NH2:7])[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]1=2)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(N)C(=O)Nc2ccccc21

Procedure:
A solution of 0.5 g (1.8 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1.7 ml of acetic anhydride is stirred for 3 hours at 65° C. The mixture was put onto water (5 ml) and extracted two times with dichloromethane (10 ml each). The combined organic layers were dried (MgSO4) and evaporated to yield 0.6 g of a light yellow foam. This compound was dissolved in a mixture of 2 ml of dichlorometane and 2 ml of trifluoracetic acid and stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then dichloromethane was added and the mixture was extracted with sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated to yield 0.31 g of (S)-1-acetyl-3-amino-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[C:27](F)=[CH:26][C:25]([NH:29][C:30]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)=O)=[C:24]([N+:38]([O-])=O)[CH:23]=1)(=[O:16])[CH3:15]>>[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[C:27]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[CH:6][CH:7]=2)=[CH:26][C:25]2[N:29]=[C:30]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[NH:38][C:24]=2[CH:23]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Reactant: O=C1OCCN1c1ccc(O)cc1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccc(N2CCOC2=O)cc1

Procedure:
One chiral form of the entitled compound was obtained as a yellow oily substance in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using 3-(4-hydroxyphenyl)-1,3-oxazolidin-2-one and N-(4-(1-acetylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyrazin-2-carboxamide enantiomer A.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
In 50 ml of methylene chloride was dissolved 2.5 g of 6-nitroindoline, and then 6.37 ml of triethylamine was added thereto. Under ice cooling, 3.51 g of methanesulfonyl chloride was added dropwise, the reaction solution was stirred at room temperature for 3 hours, and then ice-water was added thereto, followed by 1 hour of stirring. The reaction solvent was removed by evaporation under reduced pressure, a 1M aqueous hydrochloric acid solution was added to the residue, and precipitated was filtrated off, whereby 3.52 g of 1-methylsulfonyl-6-nitroindoline was obtained as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 47.3 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (50.1) (0.980 g) and NH4Cl (1.64 g) in EtOH(50 mL)—H2O (5 mL), was added iron powder (1.92 g). The mixture was heated to reflux for 1 h. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat.NaHCO3 and extracted with AcOEt (30 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. Concentration of solvent afford crude product, which was purified by column chromatography (silica gel, AcOEt:hexane=1:3) to provide aniline 50.2 (0.420 g) as a colorless solid.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-(3-methyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:17])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl

Procedure:
A mixture of 2-(4-chlorophenoxy)-2-methylpropionic acid (15.0 g) and thionyl chloride (70 ml) was boiled under reflux for 1 hour. The thionyl chloride was distilled off and the residue distilled under vacuum to give 2-(4-chlorophenoxy)-2-methylpropionyl chloride, b.p. 84-87° C. at 0.07 mbar. A solution of this chloride (14.17 g) in dichloromethane (50 ml) was added dropwise to a mixture of 1-(3-aminopropyl)imidazole (7.63 g), triethylamine (6.78 g) and dichloromethane (100 ml) at below 0° C. with stirring. After the addition, the mixture was allowed to warm up to ambient temperature and stirred at this temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (100 ml) was added and the mixture stirred for 1 hour. The mixture was separated and the aqueous layer was washed with dichloromethane. The combined organic layers were dried and evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(4-chlorophenoxy)-N-[3-(imidazol-1-yl)propyl]-2-methylpropionamide, m.p. 83-84° C.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].CN(C)[CH:12]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)[CH:14]=O>CO>[CH3:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[C:6]([C:4]#[N:5])[C:7](=[O:8])[NH:9][CH:12]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: N#CCC(N)=O
Reactant: Cc1cccc(C(C=O)=CN(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2c[nH]c(=O)c(C#N)c2)c1

Procedure:
In the manner described in Example 6, a solution of 13.7 g. of sodium methoxide and 10.7 g. of cyanoacetamide in 250 ml. of methanol and 24.0 g. of 3-(dimethylamino)-2-(3-methylphenyl)-2-propenal is refluxed overnight to give 12.0 g. of the product of the Example as a yellow solid, m.p. 254.5°-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:4]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2cccc(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)aniline (130 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (216 mg) and diisopropylethyl-amine (0.26 ml) in dichloromethane (6.5 ml) was added 1-methyl-2-chloropyridinium iodide (216 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis (tert-butoxycarbonyl) -N″- (3- (4-methoxypyridin-2-yl) phenyl) guanidine (240 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([OH:48])=O)[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:52]=[C:53]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([N:60]4[CH2:59][CH2:58][N:57]([C:53]5[CH:54]=[CH:55][CH:56]=[C:51]([C:50]([F:63])([F:64])[F:49])[CH:52]=5)[CH2:62][CH2:61]4)=[O:48])[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1cn2c(n1)CCC(c1ccccc1)C2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cn2c(n1)CCC(c1ccccc1)C2)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (276 mg; 0.86 mmol) and N-methylmorpholine (237 μl; 218 mg; 2.15 mmol) were added to a solution of 6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (200 mg; 0.72 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (162 μl; 198 mg; 0.86 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 191 mg (59%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]>Cl>[OH:3][C:2]1[N:1]=[C:4]([CH3:11])[CH:5]=[C:6]([OH:10])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(=O)c(C#N)c(N)o1
Agent: Cl
Product: Cc1cc(O)c(C#N)c(O)n1
Yield: 83.3 %

Procedure:
A suspension of 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile (6.0 g, 40 mmol) in 10% hydrochloride acid (60 mL) was heated under reflux for 4 hours. The precipitate was collected by filtration and washed with water, and then recrystallized from methanol to give 2,4-dihydroxy-6-methylnicotinonitrile (5.0 g, 83%) as a brown solid. 1H NMR (300 MHz, CD3OD): δ 12.46-12.44 (m, 1H), 11.69 (s, 1H), 5.85 (s, 1H), 2.15 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[CH:5]1[CH:4]=[CH:3][C:2]([S:8]([OH:11])(=[O:10])=[O:9])=[C:1]([OH:7])[CH:6]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccccc1O

Procedure:
100 g of phenolsulphonic acid (produced by a four-hour sulphonation of 250 parts of phenol with 270 parts of 98% sulphuric acid) are slowly reacted with a solution of 61.5 g of dimethylolurea in 75 g of water at 40° C. and the mixture is stirred for a few hours until a clear solution forms. The solution is then neutralised with 30% aqueous sodium hydroxide and then concentrated. About 150 g of a light coloured salt are produced.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([NH:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:31])[CH3:30]>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:29](=[O:31])[CH3:30])=[CH:34][CH:35]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)n(C)c3n2)cc1

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-acetamidophenylboronic acid via General Procedure A and purified via reverse phase HPLC to give 25.9 mg 134 as a white solid. MS (Q1) 529.3 (M)+.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15](SC)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][NH2:23]>C(O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([N:22]([CH3:21])[NH2:23])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Reactant: CNN
Solvent: CCO
Product: CN(N)c1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
2.9 g of 6-benzoyl-5,6,7,8-tetrahydro-3-methylmercaptopyrido[4,3-c]pyridazine and 1.5 g of methylhydrazine are heated in 20 cc of 95% ethanol in an autoclave at a bath temperature of 150° for 18 hours, and the mixture is subsequently worked up as described in Example 47. The bisqentisinate of the title compound has a M.P. 166°-168° (decomp.).
Reaction SMILES: [Br:1]/[C:2](/[CH:27]=C/C1C(C)(C)C2C(N=1)=[N+](CCCS([O-])(=O)=O)C=C(Cl)C=2)=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21]CS([O-])(=O)=O)[C:7]2[C:12]([C:13]\1([CH3:15])[CH3:14])=[CH:11][C:10](S([O-])(=O)=O)=[CH:9][CH:8]=2.[Na+:48].[Na+].[CH3:50][C:51]1([CH3:81])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:70])=[O:69])[CH:62]=[C:63]([S:64]([O-:67])(=[O:66])=[O:65])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]([CH2:72][CH2:73][CH:74]([S:76]([O-:79])(=[O:78])=[O:77])[CH3:75])=[C:52]1[CH3:80].[Na+].[Na+]>>[Br:1]/[C:2](=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH:74]([S:76]([O-:79])(=[O:77])=[O:78])[CH3:73])[C:7]2[CH:8]=[CH:9][C:10]3[C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:62][C:63]([S:64]([O-:67])(=[O:65])=[O:66])=[CH:57][C:11]=3[C:12]=2[C:13]\1([CH3:14])[CH3:15])/[CH:27]=[CH:80]/[C:52]1[C:51]([CH3:50])([CH3:81])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:69])=[O:70])[CH:62]=[C:63]([S:64]([O-:67])(=[O:65])=[O:66])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]=1[CH2:72][CH2:73][CH:74]([S:76]([O-:79])(=[O:77])=[O:78])[CH3:75].[Na+:48].[Na+:48].[Na+:48].[Na+:48].[Na+:48]
Reactant: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC(CCN1/C(=C/C=C(Br)/C=C/C2=[N+](CCC(C)S(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)C(C)(C)c2c1ccc1c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc21)S(=O)(=O)[O-]

Procedure:
Compound 27 is prepared analogously to compound 9 (Example 9), except that compounds 24 and 26 is used as a starting material.
Reaction SMILES: N#N.C[Si](C)(C)[O:5][C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CC(=O)OCC>C(#N)C>[F:22][CH:11]1[C:6](=[O:5])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10]1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 18.40 mmol) in dry acetonitrile (25 mL) was added Selectfluor® (7.55 g, 20.3 mmol) at rt. The reaction mixture was stirred at rt for 2 h then poured into EA and successively washed with aq. 1% NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes/EA, 4:1) to afford the title compound as a pale yellow solid. LC-MS-conditions 08: tR=0.55 min; [M-CH3+H]+=203.23; TLC: rf (hexanes/EA, 4:1)=0.17.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=O)[N:16]([CH:19]([CH3:21])[CH3:20])[N:15]=[N:14]1)([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[S:31])[N:16]([CH:19]([CH3:21])[CH3:20])[N:15]=[N:14]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1-n1nnn(C(C)C)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1nnn(C(C)C)c1=S
Yield: 109.4 %

Procedure:
A mixture of 5.6 g of 1-(2,6-diisopropylphenyl)-4-isopropyl-5-oxo-2-tetrazoline and 5.1 g of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) are heated at reflux for 24 hours in 60 ml of dry toluene. After evaporating off the solvent, the residue is purified by chromatography on 500 g of silica gel with hexane/ethyl acetate (19:1) as eluant. Crystallisation from hexane yields 4.2 g of 1-(2,6-diisopropylphenyl)-4-isopropyl-5-thioxo-2-tetrazoline in the form of colourless crystals, m.p. 109°-111° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN
Product: CNc1ccc([N+](=O)[O-])c(C)n1

Procedure:
6-Chloro-2-methyl-3-nitro-pyridine (0.6 g) was treated with methyl amine according to General Procedure U to give methyl-(6-methyl-5-nitro-pyridin-2-yl)-amine LCMS (m/z): 168. This was reduced under hydrogen atmosphere according to General Procedure Z to give 6,N*2*-dimethyl-pyridine-2,5-diamine (0.35 g), LCMS (m/z): 138. This was converted to 2-methyl-6-methylamino-pyridine-3-sulfonyl chloride according to General Procedure AA.