Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([Br:22])[C:13]([NH2:16])=[N:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(OCc2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
5-(Benzyloxy)pyridin-2-amine hydrochloride (52.3 g, 221 mmol) and sodium acetate (45.3 g, 552 mmol) were dissolved in acetic acid (300 mL). Bromine (11.3 mL, 221 mmol) was added slowly and stirred at ambient temperature for 18 hours. After an aqueous workup, the material was purified over silica gel to give the title compound (10.5 g, 17.0% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[N-:12]=[N+:13]=[N-:14].[Na+].CN(C)C=O.O>[Cl-].[NH4+]>[N:12]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])=[N+:13]=[N-:14]
Reactant: NS(=O)(=O)c1cnccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccncc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
4-Chloro-pyridine-3-sulfonic acid amide (4 g, 20.77 mmol) and sodium azide (13.7 g, 210 mmol) were combined. Anhydrous N,N-dimethylformamide (80 mL) and water (30 mL) were added. The mixture was stirred at 90° C. for 2 h. Upon cooling, the mixture was diluted with saturated aqueous ammonium chloride solution (200 mL). The product was extracted into ethyl acetate (6×200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product, 4-azido-pyridine-3-sulfonic acid amide (3.75 g, 18.83 mmol, 91%), as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.54 (2H, bs), 7.57 (1H, d, J=5.4 Hz), 8.68 (1H, d, J=5.5 Hz), 8.81 (1H, s).
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.CS(Cl)(=O)=O.[NH2:21][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1>ClCCl.O>[CH:33]1[C:32]([N:35]2[C:36](=[O:41])[CH2:37][O:38][CH2:39][CH2:40]2)=[CH:31][CH:30]=[C:29]([N:25]2[C:26](=[O:28])[O:27][C@@H:23]([CH2:22][NH:21][C:13]([C:11]3[S:12][C:8]([Cl:7])=[CH:9][CH:10]=3)=[O:15])[CH2:24]2)[CH:34]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
1-Methylimidazole (24.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A solution of methanesulfonyl chloride (12 g, 0.105 mol) in dichloromethane (40 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 5 hours to produce 39.2 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 90%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:10][CH:9]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=O)(C)(C)C.Cl.[CH3:31][O:32][C:33]([NH:35][CH:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:31][O:32][C:33](=[O:34])[NH:35][CH:36]([C:37]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:10][CH:9]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:38])[CH:40]([CH3:42])[CH3:41]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC(COC(F)F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CC(COC(F)F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (4 mL) and treated with HCl (4.0M in dioxane, 1 mL, 4 mmol). After 2.5 h, the solution was concentrated and the residue was treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (55 mg, 0.315 mmol) and HATU (120 mg, 0.315 mmol). The solids were suspended in DMF (3 mL) and the reaction mixture was cooled to 0° C. before triethylamine (0.25 mL, 1.43 mmol) was added in a dropwise fashion. After 30 min, the mixture was warmed to RT. After another 1 h, it was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. Then it was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (60% to 100% EtOAc/Hex) to afford the title compound (92 mg, 61%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12](C=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCOCC1>[N:1]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CN1CCC(CCCn2ccnc2)CC1
Solvent: C1COCCO1
Product: c1cn(CCCC2CCNCC2)cn1
Yield: 83.7 %

Procedure:
A mixture of 4[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde (2.12 g, 0.0095M) in dioxane (80 ml) and 2NHCl (11 ml) was refluxed for 51/2 hrs. After the reaction, the solvent was removed, water was added and the solution was basified with 2N NaOH to pH 10 and extracted with CH2Cl2 (3×50 ml). The extracts were concentrated to give an oil (1.55 g, 80%). The dihydrochloride salt of the 4[3-(1H-imidazol-1-yl)propyl]-piperidine which was crystallized from acetone has m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)[CH2:23]2)[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:32]>CCOCC>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:22]2[CH2:23][CH:24]([N:26]3[CH2:27][CH2:28][S:29][CH2:30][CH2:31]3)[CH2:25]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCSCC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CNC[C@@H](CCN1CC(N2CCSCC2)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl [(2S)-2-(3,4-dichlorophenyl)-4-(3-thiomorpholin-4-ylazetidin-1-yl)butyl]methylcarbamate (260 mg, 0.53 mmol) was dissolved in ether (15 mL) and stirred during the dropwise addition of HCl (15 mL of 4M dioxane solution). The mixture was stirred at room temperature for 1 h and then the solvent was removed by evaporation. There was obtained 270 mg (100%) of [(2S)-2-(3,4-dichlorophenyl)-4-(3-thiomorpholin-4-ylazetidin-1-yl)butyl]methylamine dihydrochloride as a white solid. 1H NMR (300 MHz, CD3OD): 1.9-2.2 (b, 2H), 2.7 (s, 3H), 3.0-4.8 (cm, 19H), 7.4 (d, 1H), 7.6 (m, 2H); LCMS: m/z 388 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16]I)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21](=[O:29])[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:29])[C:22]([CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ICCc1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C(C)(CCc1cccc(OCc2ccccc2)c1)C(=O)OCC

Procedure:
2-(3-Benzyloxyphenyl)ethyl iodide and 2-methylmalonic acid diethyl ester were used in the same manner as working example 52 (3) to give the subject compound.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7](Br)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+].[Cu+].CCOC(C)=O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Reactant: Oc1ccc(F)cc1
Agent: [Cu+]
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(F)cc2)c1
Yield: 38.2 %

Procedure:
A stirred suspension of 4-tert-butyl-2-bromobenzoic acid (0.26 g, 1.0 mmol), 4-fluoro phenol (0.22 g, 2.0 mmol), cesium carbonate (0.65 g, 2.0 mmol), copper trifluoromethanesulfonate-benzene complex (13 mg, 25 μmol), 1-naphthoic acid (0.34 g, 2.0 mmol), and 4 Å molecular sieves (0.25 g) in toluene (10 mL) and EtOAc (5 μL) was heated at 110° C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel chromatography (0%-5% MeOH—CH2Cl2) to afford 2-(4-fluorophenoxy)-4-tert-butylbenzoic acid (0.11 g, 39% yield) as a white solid. LC/MS: m/z 289.0 (M+H)+ at 3.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.3 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.14-7.05 (m, 4H), 6.84 (d, J=1.6 Hz, 1H), 1.23 (s, 9H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([NH2:18])=[O:17])=O>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:11][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:16]([NH2:18])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COc1ccc(C(N)=O)cc1C=O
Product: COc1ccc(C(N)=O)cc1C=Cc1ccc(C#N)cc1

Procedure:
The captioned compound was synthesized from 4-cyanobenzyl bromide and 3-formyl-4-methoxybenzamide by the same procedure as in the manufacturing method described in Example 2-3-6.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:9][C:8]2[N:4]([C:5]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:6]=3[C:7]=2[C:10]([O:12]C)=[O:11])[CH2:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1([CH3:19])[CH2:9][C:8]2[N:4]([C:5]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:6]=3[C:7]=2[C:10]([OH:12])=[O:11])[CH2:3]1
Reactant: COC(=O)c1c2c(n3c1CC(C)(C)C3)CCNC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2c(C(=O)O)c3c(n2C1)CCNC3=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 137l (crude, 35.4 mmol) in THF/H2O (100 mL/100 mL) was added LiOH (4.26 g, 177 mmol). See FIG. 2. The mixture was stirred at 50° C. for 1 h. Upon reaction completion, the mixture was acidified with HCl (1N) until pH<6 and concentrated to remove THF. The resulting white solid was collected by filtration and washed with cold water to give 7,7-dimethyl-1-oxo-2,3,4,6,7,8-hexahydro-1H-pyrido[3,4-b]pyrrolizine-9-carboxylic acid 137m (8 g, 91%).
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15])[NH2:13].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:20][CH2:21]3)=[O:15])[CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and indole-6-carboxylic acid (62%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br-].[C:12]1([CH2:18][CH2:19][CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:40]([N:47]1[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl>C1(C)C=CC=CC=1>[CH2:40]([N:47]1[CH2:52][CH2:51][C:50](=[CH:20][CH2:19][CH2:18][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C(CCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.5 %

Procedure:
A solution of 100 mL of 0.5M potassium bis(trimethylsilyl)amide in toluene was added to a mixture of 23.07 g (3-phenylpropyl)triphenylphosphonium bromide from Step A in 150 mL toluene in an ice bath over 15 minute with stirring under nitrogen. After stirring for 15 more minutes, a solution of 8.515 g of 1-benzyl-4-piperidone in 50 mL toluene was added over 30 minutes with stirring. The reaction mixture was stirred as it was allowed to warm to room temperature overnight. After 15 hours, the reaction mixture was poured into 200 mL cold 1N HCl. The layers were separated and the toluene layer was washed with 2×200 mL 1N HCl. The combined HCl solution and an oily interfacial layer was washed with 100 mL toluene. After adding 30 g KOH, the aqueous layer was extraced with 3×150 mL of ether. The combined ether solution was washed with 100 mL each of water and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 10˜15% ethyl acetate in hexanes having 3% (v/v) Et3N to give 8.2 g of the title compound as a colorless oil. RF: 0.38 (10% EtOAc in hexanes having 3% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.34 (d, 4.3 Hz, 4H), 7.25˜7.30 (m, 2H), 7.17˜7.21 (m, 4H), 5.19 (t, 7.2 Hz, 1H), 3.51 (s, 3H), 2.64˜2.67 (m, 2H), 2.41˜2.44 (m, 2H), 2.29˜2.35 (m, 4H), 2.18˜2.22 (m, 4H).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=O)C.[S:35]1(=[O:41])(=[O:40])[CH2:39][CH2:38][CH2:37][NH:36]1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:10]4[CH:11]=[CH:12][C:13]([N:36]5[CH2:37][CH2:38][CH2:39][S:35]5(=[O:41])=[O:40])=[CH:14][C:9]=4[N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCNC2=O)CC1
Yield: 28.4 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (152 mg) described in Preparation Example 236 and isothiazolidine 1,1-dioxide (57 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (47 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14].O=[C:16]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18].[OH-].[Na+].C([BH3-])#N.[Na+]>O>[C:17]([CH:16]([NH:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: NC1CN2CCCC(C(=O)O)N2C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CN2CCCC(C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.1 %

Procedure:
0.896 g of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate A) was dissolved in 6 ml of water. 2.4 g of 2-oxo-4-phenylbutyric acid were added and the mixture was adjusted to pH 6 with 2N aqueous sodium hydroxide solution. 0.504 g of sodium cyanoborohydride was then added and the mixture was stirred at room temperature for 22 hours. The resulting solution was applied to 10 g of Zerolit225 ion-exchange resin (H+ form). Elution with water containing 2% pyridine gave 0.98 g of a crude diastereomeric product. Crystallization from water gave a solid which was recrystallized from methanol to yield 0.36 g (22%) of 2-(1-carboxy-3-phenylpropylamino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate A) in the form of a white solid of melting point 233°-235° C. (decomposition).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>CCO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nc(-c2ccc(Cl)cc2)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 3-(4-chlorophenyl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (0.85 g, 3.16 mmol) in EtOH (30 ml) was added sodium borohydride (0.30 g, 7.90 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 10 ml of water and concentrated under vacuum. Added 100 ml water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 20% EtOAc-Hexane) to get the desired product (0.53 g, 74%).
Reaction SMILES: Cl[CH:2](Cl)[CH2:3][O:4][CH2:5][CH:6](Cl)Cl.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:4]1[CH2:5][CH2:6][C:11]([C:10]#[N:14])([C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: N#CCC#N
Reactant: ClC(Cl)COCC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCOCC1
Yield: 51.7 %

Procedure:
A mixture of 28.6 g of dichloroethyl ether, 13.2 g of malononitrile, 55.28 g of potassium carbonate and 800 ml of acetonitrile was refluxed on a steam bath for 24 hours, then filtered while hot. The filtrate was evaporated and the residue crystallized with charcoal treatment from 100 ml of ethanol, giving 9.5 g of tetrahydro-4H-pyran-4,4-dicarbonitrile as colorless plates, mp 110-112° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:14]2[CH2:19][CH2:18][N:17]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Compound 2 (150 mg, 0.41 mmol) was dissolved in DCM and cooled to 0° C. Ethanesulfonyl chloride (62.2 mg, 0.49 mmol) was added, followed by DIEA (0.21 mL, 1.22 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was diluted with DCM and washed with saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by normal phase chromatography eluting with 10-50% methanol/DCM gradient to provide Compound 91 as a white solid (0.13 g, 69%). MS: m/z 462.34 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:33]1([C:2]2[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=2[C:4]([NH:6][CH2:7][C:8]2([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[O:5])[CH2:35][CH2:34]1
Reactant: OB(O)C1CC1
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1C1CC1
Temperature: 100 °C
Yield: 30.1 %

Procedure:
2-Chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (50 mg, 0.10 mmol), cyclopropylboronic acid (44 mg, 0.51 mmol), tricyclohexylphosphine (5.7 mg, 0.02 mmol) and potassium phosphate (75 mg, 0.35 mmol) were dissolved in toluene (1 ml) and water (0.05 ml) and degassed with nitrogen for 5 minutes. Palladium acetate (2.3 mg, 0.01 mmol) was added and the mixture was heated at 100° C. for 5 hours. Palladium acetate (2.3 mg, 0.01 mmol) and tricyclohexylphosphine (5.7 mg, 0.02 mmol) were added and the reaction heated for a further 3 hours. The crude reaction mixture was diluted with dichloromethane (3 ml) and passed through a Phenomonex abw cartrige. The compound was eluted with dichloromethane (10 ml) and the filtrate was evaporated. The residue was purified by preparative plate chromatography on silica eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band, trituration of the silica with ethyl acetate, filtration and evaporation gave a colourless oil (15 mg, 30%). 1H NMR δ (ppm)(CDCl3): 7.79 (1H, d, J=7.8 Hz), 7.43 (1H, d, J=7.8 Hz), 6.00 (1H, s), 3.64 (2H, d, J=6.3 Hz), 2.97-2.89 (3H, m), 2.38-2.32 (1H, m), 2.07-1.86 (6H, m), 1.43-1.36 (2H, m), 1.28-1.14 (5H, m), 1.07-1.05 (2H, m), 0.78-0.68 (3H, m), 0.52 (2H, q, J=5.9 Hz), 0.42 (2H, q, J=5.3 Hz), 0.05 (2H, dd, J=0.0, 4.8 Hz). MS (m/e)=499.