Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][NH:34][C:33]4=[O:37])[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NCCN1CCCl
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCNCC2)cn3-c2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCN4CCNC4=O)CC2)cn3-c2ccc(F)cc2)n1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a) (4 g), 1-(2-chloroethyl)imidazolidin-2-one (1.8 g), potassium carbonate (2.1 g) and potassium iodide (0.5 g) in MIBK (80 mL) was boiled at reflux for 20 hours. After cooling, inorganic salts were filtered off and the solvent evaporated in vacuo. The title compound crystallised from ethyl acetate. Yield 3.0 g. Mp 201-203° C. 1H NMR (CDCl3): δ 2.60-2.70 (m, 4H), 2.80 (t, 2H), 3.30 (broad s, 2H), 3.35-3.45 (m, 4H), 3.55 (t, 2H), 4.40 (s, 3H), 4.65 (s, 1H), 6.35 (broad s, 1H), 7.20 (t, 2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.95 (d, 1H), 8.25 (s, 1H); MS m/z (%): 487 (MH+, 12), 142 (49), 113 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:10]=1[CH2:11][C@@H:12]([C:23]([OH:25])=[O:24])[N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(#N)C>[CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:10]=1[CH2:11][C@@H:12]([C:23]([O:25][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])[N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCCl
Product: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 7A from 420 mg (0.68 mmol) of the compound from Example 70A, 9.77 mg (0.08 mmol) of DMAP, 173 mg (1.6 mmol) of benzyl alcohol and 184 mg (0.96 mmol) of EDC in 8 ml of acetonitrile.
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[NH:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[F:20])[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1)=[O:3].C(N=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[F:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([CH2:10][N:9]1[C:5]3[N:6]=[CH:7][NH:8][C:4]=3[C:2](=[O:3])[NH:1][C:37]1=[S:38])=[CH:12][N:13]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2c(F)cccc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)c2c(F)cccc21
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A solution of tert-butyl 3-({[5-(aminocarbonyl)-1H-imidazol-4-yl]amino}methyl)-4-fluoro-1H-indole-1-carboxylate (0.17 g, 0.45 mmol, obtained from Example 11(b)) and benzoyl isothiocyanate (0.073 mL, 0.54 mmol) in CH2Cl2 (5 mL) was stirred for 3 h 20 minutes and then evaporated. Ammonia (7 M in MeOH, 4 mL) was added to the residue and the mixture was heated to 80° C. for 2 h and then evaporated. Purification by flash chromatography using MeOH (2%) in CHCl3 gave the title compound (0.089 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: BrCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
A solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 44.6 μl (0.375 mmol) benzyl bromide and 32 μl (0.375 mmol) N-ethyl-diisopropylamine in 2 ml dioxane is heated at 100° for 90 h. The reaction mixture is concentrated and the residue taken up in 0.1 M sodium hydroxide solution and extracted with dichloromethane. Preparative HPLC affords (2-benzylamino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=O)C.[NH2:15][C@@H:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[O:18]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:5]([OH:4])=[C:6]([CH:10]=1)[C:7]([NH:15][C@H:16]([C:17](=[O:18])[NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:9]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)C[C@H](NC(=O)c1cc(Cl)ccc1O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 24.8 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and (S)-2-amino-4-methyl-N-[3,5-bis-(trifluoromethyl)phenyl]pentanamide as the raw materials, the same operation as the Example 302(2)-(3) gave the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-:19].[K+].[K+].OO>O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:19])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzonitrile (3.6 g, 16.1 mmol), dimethylsufoxide (25 mL), potassium carbonate (2.1 g, 15.2 mmol), and 3 mL of 30% hydrogen peroxide solution. Stir 18 h at ambient temperature. Dilute with 100 mL of water, extract with ethyl acetate (3×100 mL). Wash the organic phase with 100 mL of water, and 50 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via aBiotage Flash 40L system using 75:25 hexanes/ethyl acetate as eluting solvent to give 3.0 g (77%) of the title compound: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.88 (m, 4H), 7.12 (m, 4H), 5.29-5.14 (br m, 2H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[CH:44]([CH3:45])[CH2:43][CH2:42][CH2:41][C:40]=1[CH3:46])(=O)=O>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:44]([CH3:45])[CH2:43][CH2:42][CH2:41][C:40]=4[CH3:46])=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)C(C)CCC1
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)C(C)CCC1

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 2, Step B (0.500 g, 1.17 mmol) and 2,6-dimethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.401 g, 1.29 mmol) were reacted in the manner of Example 2, Step C. Purification by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane, followed by recrystallization from petroleum ether (−20° C.) afforded the title compound as white crystals, m.p. 133–135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:24])[C:6]=2[CH:40]=1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[C:8](=[O:21])[N:7]([CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:43])[CH2:32][CH2:33]3)=[O:24])[C:6]=2[CH:40]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCNCC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCN(C)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 98.0 mg (0.17 mmol) 2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenyl-N-(2-piperazin-1-yl-ethyl)acetamide (Example 131) in 4 ml of THF was mixed with 5.54 mg (0.19 mmol) of paraformaldehyde and 170 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.42 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][C:20](=[O:22])[CH3:21])[NH:14][C:15](=O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>O1CCOCC1>[Cl:34][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:19][C:20](=[O:22])[CH3:21])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
To a suspension of N-[6-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (0.77 g, 2.58 mmol) and DIEA (1.34 mL, 7.74 mmol) in dioxane (25 mL) was added POCl3 (0.73 mL, 7.74 mmol). The mixture was heated to 80° C. for 30 minutes. After the removal of solvent, the residue was dissolved in ethyl acetate (200 mL) and the solution was filtered through a short column with silica gel. The column was additionally washed with ethyl acetate. The filtrate and washings were combined and concentrated. The precipitate formed was isolated by filtration to give the pure title compound as a brown solid (0.43 g, yield 43%) which was characterised as follows: MS (m/z) 317.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[N+:9]([O-:22])[C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2)c[n+]1[O-]

Procedure:
A solution of 3-phenyl-6-methyl pyridine (2.36 g, 13.95 mmol), in CH2Cl2 (40 mL) at 0° C. was treated with MCPBA (3.58 g, 13.95 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added and the reaction was extracted with CH2Cl2 (20 mL). The organic extracts were dried (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH:18]([CH3:28])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:22]1([NH:21][C:19](=[O:20])[CH:18]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)[CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(Br)C(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)Nc1ccccc1
Yield: 68.8 %

Procedure:
To 30 ml of acetone were added 1.06 g of 4-(4-cyanophenoxy)-phenol, 0.99 g of α-bromopropionanilide and 0.83 g of anhydrous potassium carbonate, and the mixture wask subjected to reflux for 16 hours with stirring. After the reaction mixture was cooled and separated from inorganic salts through filtration, acetone was distilled away therefrom. The residue was purified through a column-chromatography [silica gel, developed with ethyl acetate/n-hexane=1/1(V/V)] to give 1.07 g of the title compound (yield 60%), which was recrystallized from a mixed solvent of benzene-n-hexane to afford a crystal of melting point 133°-134° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:11]3=[O:34])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:46][CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:11](=[O:34])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:46][CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH2:3][CH2:2]4)[CH:9]=3)[N:14]=2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: COc1cc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccc(N4CCCN(CC5CCOCC5)CC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
2-(6-(1,4-Diazepan-1-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (EXAMPLE 1i) (30 mg, 0.064 mmol), (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (35 mg, 0.128 mmol) and DIPEA (17 mg, 21 μl, 0.128 mmol) were dissolved in DMF (1 mL) and stirred at room temperature overnight. Purification by preparative HPLC afforded 2-{2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-[4-(tetrahydropyran-4-ylmethyl)perhydro-1,4-diazepin-1-yl]-4H-quinazolin-3-yl}-N-isopropylacetamide (EXAMPLE 11a) (5 mg, 0.0088 mmol, 14%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][C@@H:23]2[CH2:28][O:27][C@@H:26]([CH2:29][OH:30])[CH2:25][O:24]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][C@@H:23]2[CH2:28][O:27][C@@H:26]([CH:29]=[O:30])[CH2:25][O:24]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@H](CO)CO2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@H](C=O)CO2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A solution of oxalyl chloride (14.2 mL, 165.5 mmol, Spectrochem) in DCM (30 mL) was cooled to −78° C. and was added DMSO (21.1 mL, 298 mmol, Spectrochem) drop wise. The reaction mixture was stirred for 20 minutes at the same temperature and a solution of rac ((2S*,5S*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (20 g, 66.2 mmol, Preparation #11: Step c) in DCM (60 mL) was added slowly. The reaction mixture was stirred at the same temperature for another 1 h and quenched with TEA (26.7 mL, 364.2 mmol). The reaction mixture was warmed to RT, diluted with DCM (50 mL) and washed successively with 1N HCl (2×150 mL), saturated sodium bicarbonate (2×100 mL) and brine (2×100 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure to afford racemnic ((2S*,5R*)-5-formyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 20 g (crude, 100%); 1H NMR (400 MHz, CDCl3): δ 9.55 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.37 (d, J=7.6 Hz, 2H), 4.01-3.92 (m, 5H), 3.76 (m, 1H), 3.53-3.42 (m, 2H), 2.45 (s, 3H); MS m/z: 301.3 (m+H)+
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[CH:46]=[CH:45][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)[O:37][C:38]=2[CH3:39])=[C:30]([O:47][CH3:48])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:36]1[O:37][C:38]([CH3:39])=[C:34]([CH2:33][O:32][C:31]2[CH:45]=[CH:46][C:28]([CH2:27][O:1][C:2]3[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][CH:14]=4)[N:3]=3)=[CH:29][C:30]=2[O:47][CH3:48])[N:35]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (3.00 g), potassium carbonate (2.52 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.30 g, yield: 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].CO>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: c1cc2cc[nH]c2cn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1c(Cl)cccc1Cl)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
1H-Pyrrolo[2,3-c]pyridine (0.5 g, 4.2 mmol) was added to a stirred suspension of aluminium chloride (2.82 g, 21.1 mmol) in dry dichloromethane (100 mL) and the mixture was stirred at room temperature for 1 hour. This was followed by drop-wise addition of 2,6-dichloro benzoyl chloride (4.42 g, 21.1 mmol). The resulting reaction mixture was stirred at room temperature for 8 hours. Methanol (25 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The resulting residue was neutralized using aqueous sodium bicarbonate solution followed by partitioning with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using ethyl acetate and hexane gradient as eluent afforded (2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (0.5 g, 41.66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][SH:12].[C:13](=O)(OC1C=CC=CC=1)[O:14]C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:10][CH2:11][S:12][C:13]1=[O:14]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: SCCNCc1ccccc1Cl
Product: O=C1SCCN1Cc1ccccc1Cl
Yield: 43.9 %

Procedure:
The procedure of Example 2 is followed 5.05 g (0.025 mol) of N-(2-chlorophenylmethyl)cysteamine are reacted with 5.35 g (0.025 mol) of diphenyl carbonate and then worked up. The product is purified by column chromatography (by using Kieselgel 60 of 230-400 mesh as sorbent and chloroform as eluent) to obtain 2.5 g (43.9%) of the title compound, nD30 =1.600.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
To a solution of (3R)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (4.00 g, 11.6 mmol) (obtained as described in Reference Example 52(2)) in dimethylformamide (120 ml) was added sodium azide (831 mg, 12.8 mmol), and the mixture was stirred in an oil bath (100° C.) for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford (3S)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (3.43 g, yield 100%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:23]3[CH:32]=[C:31]([CH3:33])[C:26]([C:27]([O:29]C)=[O:28])=[CH:25][N:24]=3)[C:13]=2[O:14]COCC[Si](C)(C)C)=[CH:5][CH:4]=1)#[N:2].CO.[Li+].[OH-]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:23]3[CH:32]=[C:31]([CH3:33])[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cnc(-n2ncc(-c3ccc(C#N)cc3)c2OCOCC[Si](C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Combined methyl 6-(4-(4-cyanophenyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-1-yl)-4-methylnicotinate (8.67 g, 25.96 mmol), methanol (50 mL), water (50 mL) and LiOH (3.27 g, 77.87 mmol). The reaction mixture was stirred at room temperature for 6 h and at 50° C. overnight. The reaction mixture was concentrated to remove most of the methanol and then the pH was adjusted to 3 by addition of 3N HCl to give a solid. The solid was collected by filtration and dried in vacuum to give the title compound (4.3 g, 51.76%).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].C(N(CC)CC)C.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>ClCCCl>[C:3]([CH2:2][NH:1][S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])#[N:4]
Reactant: N#CCN
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCS(=O)(=O)NCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
Aminoacetonitrile (14.25 g, 92.5 mmoles) was dissolved in 1,2-dichloroethane (150 ml) and the reaction was placed under N2. Triethylamine (32.76 g, 324 mmoles) was added and the reaction was cooled to zero degrees Celsius. A solution of propane-1-sulfonyl chloride (13.19 g, 92.5 mmoles) in 1,2-dichloroethane (20 ml) was added dropwise and the reaction was allowed to warm to room temperature and was stirred for 16 hours. Thin-layer chromatography showed the presence of a new product with a higher Rf. The solvent was removed in vacuo and the crude product was submitted to flash chromatography (methylene chloride:ethyl acetate, 9:1) to yield 10.56 g of propane-1-sulfonic acid cyanomethyl-amide. 1HNMR (CDCl3): 5.40 (s, 1H), 4.11 (s, 2H), 3.15 (m, 2H), 1.89 (q, 2H), 1.10 (t, 3H).