Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].[I:21]I.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([I:21])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc2[nH]ncc12
Reactant: II
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Cl)nc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
In a 1 L single necked flask were charged 6-chloro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (10 g, 44.3 mmol) and dioxane (400 ml). To this resulting suspension were added a saturated solution of sodium hydrogen carbonate (0.5M, 260 ml) and iodine (11.2 g, 44.3 mmol). The reaction mixture was stirred at room temperature for 24 hours, iodine was then added (25 g, 97.5 mmol) and stirring was pursued for 48 hours. Next an aqueous sodium thiosulfate solution (0.9M) was added until complete decolouration and was poured into a solution of ice and HCl at pH=2. The mixture was filtered to afford the title compound as a yellow solid (14.7 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:5]2[C:6]3[CH:12]([CH2:13][CH2:14][NH2:15])[CH2:11][CH2:10][C:7]=3[CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:16]=[C:5]2[C:6]3[CH:12]([CH2:13][CH2:14][NH:15][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH2:11][CH2:10][C:7]=3[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c3c(ccn2n1)CCC3CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c3c(ccn2n1)CCC3CCNC(=O)C1CC1
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a mixture of 2-(2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine (69.7 mg, 0.324 mmol) and triethylamine (90.3 μL, 0.648 mmol) in tetrahydrofuran (3 mL) was added cyclopropanecarbonyl chloride (35.3 μL, 0.389 mmol) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (68.0 mg, yield 74%).
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:24]=[CH:23][C:22]3[S:21](=[O:26])(=[O:25])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH3:27])[C:13]=3[CH:12]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:24]=[CH:23][C:22]3[S:21](=[O:25])(=[O:26])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH3:27])[C:13]=3[CH:12]=2)/[C:8]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(N)n1
Reactant: CN1c2ccccc2S(=O)(=O)c2ccc(/C(=C\C3CCCC3)C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2ccccc2S(=O)(=O)c2ccc(/C(=C\C3CCCC3)C(=O)Nc3ccn(C)n3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
480 mg of (E)-3-cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acrylic acid, 122 mg of commercial 1-methyl-1H-pyrazol-3-ylamine and 0.76 ml of N,N-diisopropylethylamine are dissolved in 7 ml of dimethylformamide. 571 mg of HATU and 204 mg of HOAT are added, and the mixture is stirred at room temperature for one hour. The reaction mixture is then diluted by addition of 100 ml of ethyl acetate and washed five times with in each case 30 ml of water. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane (100%)=>:ethyl acetate (100%). This gives 360 mg of (E)-3-cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)acrylamide.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH3:14])[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:3].[CH3:17][NH:18][NH2:19]>CO>[CH3:17][NH:18][NH:19][C:2]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH3:14])[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:3]
Reactant: CNN
Reactant: CON1C(C)(C)CC(OC(=O)Cl)CC1(C)C
Solvent: CO
Product: CNNC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1

Procedure:
The title compound is prepared by reacting the compound of Example 27 (1 mole) with methylhydrazine (1.1 mole) in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Cl
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C=Cc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To 4-chloro-3-methylaniline (3.33 g, 19.98 mmole) in dichloromethane (100 mL) and pyridine (20 mL) was added cinnamoyl chloride (2.83 g, 19.98 mmole) at 0° C. The mixture was stirred at room temperature for 2 h. Solvent and pyridine were removed by rotary evaporator under reduced pressure. The residue was diluted with ethyl acetate and washed 1N HCl (2×100 mL), water (2×100 mL), sodium bicarbonate solution (2×100 mL) and dried over sodium sulfate. After removing solvent a white solid was recovered (5.38 g, 99% yield). The product was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.76-7.24 (m, 10H), 6.58 (d, 1H), 2.55 (s, 3H); MS (ESI) m/z: Calculated for C16H14ClNO: 271.1. found: 272 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O-])(=[O:25])C.[Na+]>CN(C)C=O>[CH2:6]([O:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([CH:23]=[O:25])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(COc2cccc3occc23)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c2ccoc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Dry N,N-dimethylformamide (12.1 g, 166 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (11.4 g, 75 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min at 10° C., a solution of 4-benzyloxy-benzofuran (9.3 g, 41 mmol) in N,N-dimethylformamide (9 ml) was added dropwise within 30 min. The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 100° C. After 10 min at 100° C. the mixture was heated at 85° C. for 3 h, cooled to 10° C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate and water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 1.8 g (7 mmol, 17%) of the title compound as yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].C(=O)([O-])[O-].[K+].[K+].[H-].[Na+].[Br:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:25])[CH3:24]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Br:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]([CH2:2][C:3]([CH3:5])=[CH2:4])[C:23](=[O:25])[CH3:24]
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1cccc(F)c1Br
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)CN(C(C)=O)c1cccc(F)c1Br
Temperature: 75 °C
Yield: 102.7 %

Procedure:
2 g of 3-bromo-2-methylpropene, 1.9 g of potassium carbonate and 570 mg of sodium hydride (dispersion in oil at 60%) are added to a solution of 3 g of N-(2-bromo-3-fluorophenyl)acetamide in 25 ml of toluene. The reaction mixture is placed under an argon atmosphere and heated at 75° C. for 16 hours. The reaction mixture is treated with a mixture of water and ethyl acetate, and the organic phase is then washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 3.8 g of N-(2-bromo-3-fluorophenyl)-N-(2-methylallyl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.[CH:11]1(N)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:1][C:2]2[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCCCC1
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and cycloheptylamine according to Method G+H.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCCC.CCOC(C)=O>[C:18]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1cccnc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (60 mg, 70%); 1H NMR δ (CDCl3): 8.62-8.63 (m, 1H), 8.48-8.46 (m, 1H), 7.68-7.64 (m, 1H), 7.21-7.17 (m, 1H), 2.46 (t, J=7.21 Hz, 2H), 1.63 (p, J=7.15 Hz, 2H), 1.49-1.3 (m, 4H), 0.93 (t, J=7.22 Hz, 3H); LCMS m/z: 173.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[CH2:12][CH2:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)C.[OH-].[K+].Cl>C1COCC1.O>[O:21]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCOC(=O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
To a solution of 6.17 g 4-(4-oxo-4-phenyl-butyryl)-benzoic acid ethyl ester from Step 1 in 100 mL THF was added a solution of 3.86 g (69 mmol) potassium hydroxide in 110 mL water. The reaction was heated to reflux for 4.5 hr and allowed to cool. The reaction was transferred to an Ehrlenmeyer flask and cooled to 0° C. in an ice bath. Concentrated hydrochloric acid was added dropwise until a solid precipitated. The solid was collected by filtration and dried to afford 2.59 g (9.1 mmol) 4-(4-oxo-4-phenyl-butyryl)-benzoic acid.
Reaction SMILES: CS[C:3](=[N:12][CH3:13])[N:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[NH2:14][OH:15].Cl.NO>>[C:6]1([N:4]([CH3:5])[C:3]([NH:12][CH3:13])=[N:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN=C(SC)N(C)c1ccccc1
Reactant: NO
Agent: Cl
Product: CNC(=NO)N(C)c1ccccc1

Procedure:
The above compound is also made by the reaction of S-methyl-N-phenyl-N,N'-dimethylisothiourea (3.3g, 0.017 mol) with hydroxylamine (0.088 mol) generated from hydroxylamine hydrochloride (5.86g, 0.088 mol) as in Example 1. The compound was confirmed by comparison of its NMR and thin layer chromatographic Rf values with a previously prepared compound. The yield was calculated to be about 1%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:18]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=3[CH:18]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)N(C(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isopropyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (26%). mp 231° C.; LCMS: m/z=565.57 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1H, J=8.8 Hz), 8.06 (s, 3H), 7.65 (m, 1H), 7.63 (m, 1H), 6.89 (s, 1H), 6.56 (d, 1H, J=2.3 Hz), 6.48 (m, 1H), 4.69 (m, 1H), 3.94 (s, 3H), 3.91 (m, 4H), 3.18 (m, 4H), 2.39 (m, 1H), 2.21 (m, 2H), 1.84 (m, 1H), 1.50 (m, 1H), 1.43 (m, 6H), 1.36 (s, 1H), 1.30 (s, 3H), 1.26 (s, 1H), 1.02 (d, 3H, J=7.1 Hz).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:14]1[CH2:15][CH:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:17]1
Reactant: COc1ccccc1NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccccc1NC1CNC1
Yield: 81.2 %

Procedure:
A solution of 2.0 g of (1-benzhydryl-azetidin-3-yl)-(2-methoxyphenyl)-amine in 30 mL of methanol was added to a suspension of 10% Pd/C in methanol. 4.0 g of ammonium formate was added portion wise and the reaction was heated under reflux for 2 h. The mixture was cooled, filtered over celite, the filtrate was evaporated. The residue was triturated with CH2Cl2, and filtered. The filtrate was evaporated to give 0.840 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)=[CH:25][CH:26]=3)[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: FC(F)(F)c1cccc(-c2ccc(CBr)cc2)c1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4cccc(C(F)(F)F)c4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-3-(trifluoromethyl)biphenyl in N,N-dimethylformamide. Column chromatography provided a light yellow glass. 1H NMR: δ 7.93 (dm, J=9.0 Hz, 2H), 7.78 (br s, 2H), 7.72 (d, J=7.5 Hz, 1H), 7.49-7.62 (m, 4H), 7.28 (dm, J=8.7 Hz, 2H), 7.07 (dm, J=9.0 Hz, 2H), 3.98 A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.40 (B of AB, J=13.7 Hz, 1H). MS (m/e): 520.0 (M−H)−. Anal: Calc for C24H18F3NO5S2: 55.27% C, 3.48% H, 2.69% N; Found: 55.23% C, 3.70% H, 2.69% N.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.[ClH:38]>ClCCl>[ClH:38].[CH3:35][NH:34][C:33](=[O:36])[CH2:32][NH:31][C:30](=[O:37])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([NH:2][CH3:1])[CH2:15][CH2:14]4)[C:28]=3[C:27]1=2
Reactant: CNC(=O)CNC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CNC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(NC)CC4)c3c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl N-methyl-N-(4-[[(3R)-3-([[(methylcarbamoyl)methyl]carbamoyl]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (130 mg, 0.24 mmol, 1.00 equiv) in 5.5 mL of dichloromethane was added concentrated hydrochloric acid (0.5 mL) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath and concentrated under reduced pressure to afford N-methyl-2-[2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]acetamido]acetamide hydrochloride (105 mg, crude) as a yellow oil. MS: m/z 432 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:14]([CH3:16])[NH2:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=O)C.[OH-].[K+]>C(O)(=O)C>[CH3:16][N:14]1[C:7]2=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=[C:6]2[C:4](=[O:3])[NH:15]1
Reactant: CCOC(=O)c1cnc(SC)nc1N(C)N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1ncc2c(=O)[nH]n(C)c2n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
4-(N-Methyl-hydrazino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6.0 g, 0.025 mol) was added to a 10% aqueous potassium hydroxide solution. The reaction mixture was heated to reflux for 15 minutes, and then cooled to room temperature. The system was acidified with a 25% aqueous acetic acid solution and the formed product was isolated by filtration. Crude product was recrystalized from a 3:1 ethanol-water mixture to give 4.6 g (95%) of pure 1-methyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one; LC/MS (m/e)=197.0 (MH+), Rt=1.30 min.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].C(N(CC)C(C)C)(C)C.[CH:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35]>C(#N)C>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:34]=[O:35])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C=O)CC1
Reaction time: 2 h

Procedure:
To as solution of (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride (0.12 mmole) from experiment K4 in acetonitrile (1.0 ml) was added at 22° C. N,N-diisopropylethyl amine (0.38 mmole) and p-nitrophenyl formate (0.14 mmole) and stirring was continued for 2 h. The mixture was evaporated, the residue partitioned between ethyl acetate and aqueous sodium carbonate, the organic layer was washed with water, dried and evaporated. The residue was purified by prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-formyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 482.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:13]2[CH:24]=[C:25]([C:28]([O:30]CC)=[O:29])[CH:26]=[CH:27][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[CH2:3]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:13]2[CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=[CH:27][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc2nc(Cc3ccccc3)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nc(Cc3ccccc3)n(Cc3ccc(Cl)cc3Cl)c2c1
Yield: 77.9 %

Procedure:
Ethanol (80 ml) and 10% sodium hydroxide aqueous solution (37 g) are added to 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole (0.48 g) (example 12), and the solution is refluxed for 4 hours. After the reaction solution is cooled, its acidity is adjusted to pH 6 with 10% hydrochloric acid. The sediment is gathered, is washed with water, is dried under reduced pressure, and thus, 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole (0.35 g) is obtained.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7](Cl)[N:6]=1.O.[C:14](OCC)(=[O:16])C>CO>[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:16][CH3:14])[N:6]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3.24 g of sodium methoxide dissolved beforehand in 13 ml of methanol are added dropwise to a solution of 11 g of 2,4,6-trichloropyrimidine in 140 ml of methanol cooled to 0° C. in an ice bath. The ice bath is removed. The reaction medium is stirred at 0° C. for 45 minutes and then the cooling bath is removed so as to allow the temperature to rise to ambient temperature. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 30 ml of water and 100 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give an oil which is left to crystallize for 24 hours at ambient temperature. The product crystallizes in the form of needles in the middle of an oil. The needles are separated, so as to give 3.94 g of 2,4-dichloro-6-methoxypyrimidine, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCC(O)CC1)c1ccccc1
Temperature: 25 °C
Yield: 3.1 %

Procedure:
A mixture of 4-hydroxypiperidine (550 mg, 5.4 mmol), 4-chlorobutyrophenone (490 mg, 2.7 mmol), NaI (160 mg), K2CO3 (760 mg) and toluene (25 mL) was refluxed for 24 h, cooled to rt, filtered and washed with hexane (2×10 mL). The filtrate was evaporated, and the residue was chromatographed over silica gel (EtOAc-EtOH-NH4OH, 60:40:2) to give 21 mg (3%) of the free base as a yellow powder, mp 101-2° C. 1H NMR (CDCl3-D2O): 1.50-1.57 (m, 2H), 1.83-1.98 (m, 3H), 2.08-2.17 (m, 3H), 2.397 (t, 2H, J=7), 2.73-2.78 (m, 2H), 3.00 (t, 2H, J=7), 3.60-3.70 (m, 1H), 7.43-7.56 (m, 3H), 7.96-7.98 (m, 2H). Analysis, Calcd for C15H21NO2: C, 72.84, H, 8.56, N, 5.66; Found: C, 72.31, H, 8.45, N, 5.32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])(=[O:10])=[O:9].[CH2:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH2:19]>CN(C)C=O.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>[CH3:15][C:12]([NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:19][CH:18]=[CH2:17])(=[O:10])=[O:9])([CH3:16])[CH2:13][CH3:14]
Reactant: CCC(C)(C)NS(=O)(=O)c1ccccc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1ccccc1S(=O)(=O)NC(C)(C)CC
Temperature: 110 °C
Yield: 92.7 %

Procedure:
To a solution of 2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide (5.00 g, 16.3 mmol) in dimethylformamide (dry, N2-degassed, 20 mL) were added allyltribuylstannane (6.07 mL, 19.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (189 mg, 0.163 mmol). The mixture was heated at 110° C. for 15 h. The reaction was concentrated in vacuo and the residue was chromatographed (silica, 40% dichloromethane/hexanes to dichloromethane gradient) to provide N-(1,1-dimethylpropyl) 2-(2-propenyl)benzenesulfonamide (4.04 g, 92%) as an off-white solid: LCMS (neg. ion spectrum) m/z 266.