Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>CN(C)C=O.ClCCl>[CH:7]1([C:12]([N:16]([CH3:15])[O:17][CH3:18])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)C1CCCC1
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCC1
Reaction time: 2 h

Procedure:
Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a stirred solution of cyclopentanecarboxylic acid (4.56 g, 40 mmol) and dimethylformamide (2 drops) in dichloromethane (20 ml) under nitrogen at room temperature. After 2 hours, the reaction mixture was evaporated under reduced pressure and the residual oxalyl chloride removed azeotropically using dichloromethane. The resulting oil was dissolved in dichloromethane (50 ml) and N,O-dimethylhydroxylamine (4.3 g, 44 mmol) added portionwise to the stirred solution. The resulting mixture was cooled using an ice bath, pyridine (7.1 ml, 88 mmol) added, the cooling bath removed and stirring continued for 18 hours. The reaction mixture was then diluted with dichloromethane (50 ml), washed with 5% aqueous citric acid solution (×2) and saturated brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a solvent gradient of methanol:dichloromethane (0:100 to 2:98), to furnish the required amide as an oil. Rf 0.50 (SS 18). Found: C,59.28; H,9.74; N,8.81. C8H15NO2 ; 0.25 H2O requires C,59.41; H,9.66; N,8.66%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[OH:23][C@H:24]1[C@H:28]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH2:27][NH:26][CH2:25]1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C@@H:28]([N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)[C@H:24]([OH:23])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: O[C@@H]1CNC[C@H]1n1ccnn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1c(F)c(N2C[C@@H](O)[C@H](n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 110 °C

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (63 mg, 0.21 mmol), trans-3-hydroxy-4-(1,2,3-triazol-1-yl)-pyrrolidine hydrochloride (100 mg, 0.52 mmol) and diazabicycloundecane (79 mg, 0.52 mmol) in pyridine was heated at 110° C. for 20 h. The reaction mixture was concentrated and the residue was triturated with water. The separated solid was filtered, washed with water and acetonitrile and dried under vacuum at 40° C. Yield: 35 mg (40%), m.p. 261°-165.5° C. 1H NMR (TFA) δ: 1.33-1.51 (m, 4H), 4.24 (m, 2H), 4.60 (m, 2H), 4.92 (m, 1H), 5.20 (m, 1H), 5.79 (m, 1H), 8.59 (d, 1H), 8.78 (s, 1H), 9.15 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
1.9 mL (6 mmol) of titanium isopropoxide and 1 g (10 mmol) of (R)-1-tert-butoxycarbonyl-pyrrolidine-2-carbaldehyde are added to a solution of 1 mL (30 mmol) of cyclopropylamine in 5 mL of anhydrous methanol. The solution is stirred for 5 hours at room temperature then 246 mg (605 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. Water is added and the compound is extracted with diethyl ether. The organic phases are dried over magnesium sulfate, filtered and evaporated to give 1.17 g (97%) of (R)-1-tert-butoxycarbonyl-2-cyclopropylaminomethyl-pyrrolidine in the form of a colourless oil.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:26]3[CH2:25][CH2:24][N:23]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:28][CH2:27]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Solvent: O
Product: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A mixture of 3.5 g of 2-tert.-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, and 5.8 g of N-carbethoxypiperazine is heated at 180° for 2 hours, cooled and poured into water. The solid is filtered, washed with water and crystallised from isopropyl alcohol to give 2-tert-butyl-5-[4-carbethoxypiperazin-1-yl]-6-nitrobenzothiazole, melting at 100°-102°.
Reaction SMILES: [CH:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH:1]1([C:7]2[S:9][CH:11]=[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)C1CCCCC1
Solvent: CCO
Product: CCOC(=O)Cc1csc(C2CCCCC2)n1
Yield: 71.3 %

Procedure:
A mixture of cyclohexanethiocarboxamide (5.0 g), ethyl 4-chloroacetoacetate (5.74 g), ethanol (50 ml) was heated under reflux for 1 hour. After dilution with water, mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel with ethyl acetate-hexane (1:4) to yield ethyl 2-cyclohexyl-4-thiazoleacetate as an oil (6.3 g, 70.9%). IR (Neat): 1735, 1255 cm-1. NMR (CDCl3)δ: 1.28 (3H, t, J=7 Hz), 1.2-2.3 (10H, m), 2.97 (1H, m), 3.77 (2H, s), 4.17 (2H, q, J=7 Hz), 7.0 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[S:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of 24 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminocarbonylisoxazole and 39 grams of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in 400 ml of toluene was refluxed for three hours. Upon cooling of mixture to room temperature, all the solid was filtered off and the filtrate was concentrated. The resulting crude product from the filtrate was then purified on a silica gel column with 3% methanol in dichloromethane to yield 16.5 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminothiocarbonylisoxazole.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:11][C:12]([NH2:14])=[O:13]>C1COCC1.CN(C=O)C>[CH:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=1)=[O:7]
Reactant: O=Cc1c[nH]cn1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)Cn1cnc(C=O)c1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in anhydrous THF (32 mL) and DMF (8 mL) was treated with sodium hydride (60% dispersion in mineral oil, 880 mg, 22 mmol) for 5 mins. 2-Bromoacetamide (3.59 g, 26 mmol) was added and the reaction was stirred continuously overnight. The THF was concentrated, loaded on a silica column, and eluted with 20% methanol in dichloromethane. The solvent was evaporated to yield 2.70 g of the product as a white solid (88.2%). HPLC Method D, r.t.=1.5 min, (96.4% purity at 256 nm). LC/MS calculated mass=153.14, [M−H]−=152, [M+H]+=154.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.II.C1(C)C=CC=CC=1.C1[O:35][CH:33]1C>O>[CH3:33][O:35][C:21]1[CH:20]=[CH:19][C:18]2[C:7]3[C:6](=[CH:5][CH:4]=[CH:3][CH:8]=3)[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:17]=2[CH:22]=1
Reactant: CC1CO1
Reactant: COc1ccc(-c2ccc(OC)cc2-c2ccccc2)cc1
Agent: II
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c3ccccc3c3ccc(OC)cc3c2c1
Reaction time: 18 h
Yield: 72 %

Procedure:
12.4 g (42.7 mmol) of 4,4′dimethoxy-o-terphenyl and 16 g (63.0 mmol) iodine chips was placed in a 250 mL reaction vessel. 200 mL of toluene was added followed by 30 mL of propylene oxide. The photoreactor was set up with a condenser cooled by a circulating chiller. A 400 W medium pressure mercury lamp was used as the light source. The reaction vessel was placed in a cabinet. The lamp was ignited and the chiller temperature was set such that the water exiting the reactor was maintained at between 20° C. and 25° C. (monitored by a thermocouple attached the exit stream). The reaction was left on for 18 hours. A solid was filtered off and washed with hexanes, only recovered 2.2 g of material. The filtrate was diluted with toluene and washed with sodium sulfate solution. The aqueous layer was back extracted with toluene and the organic layers were dried over magnesium sulfate, filtered, and evaporated. Material was dissolved in toluene and added sodium sulfite solution and stirred. The layers were separated, the aqueous layer extracted with toluene and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 0 to 100% ethyl acetate/hexane. 8.8 g material (72%) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH:16]=O)[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:18]([C:21]1[S:22][CH:23]=[C:24]([C:26]([N:28]2[CH2:33][C:32]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[O:31][CH2:30][CH2:29]2)=[O:27])[N:25]=1)([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(O)(=O)C.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][N:36]2[CH2:37][CH2:38][C:32]3([O:31][CH2:30][CH2:29][N:28]([C:26]([C:24]4[N:25]=[C:21]([CH:18]([CH3:19])[CH3:20])[S:22][CH:23]=4)=[O:27])[CH2:33]3)[CH2:34][CH2:35]2)[CH:12]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)cs1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4csc(CCO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-3-carbaldehyde (0.6 g) (example 278, step c) was added to (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (0.94 g) (example 22, step b) in a mixture of N-methyl-2-pyrrolidinone (5 mL) and acetic acid (0.13 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.71 g) was then added and the mixture stirred overnight. The reaction was poured into water (100 mL), the pH was adjusted to 8 using saturated sodium bicarbonate solution and the resulting aqueous solution extracted with ethyl acetate (3×100 mL). The combined organic solutions were washed with water (3×100 mL), brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 77.5:17.5:5 i-hexane:ethyl acetate:triethylamine to 47.5:47.5:5 i-hexane:ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 0.8 g.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.C([N:23](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:15])[NH:16][NH2:23])=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncncc12
Reactant: CCN(CC)CC
Agent: NN
Solvent: O
Solvent: CCO
Product: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
610 mg (approx. 1.92 mmol, purity 86%) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 10 ml of ethanol and cooled to 0° C. 777 mg (7.68 mmol) of triethylamine and 120 mg (1.920 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 590 mg (purity 89%, 95% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:11])SCC)[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:21]=1[C:22]([NH:24][CH:25]([CH:27]1[CH2:29][CH2:28]1)[CH3:26])=[O:23].S([O-])([O-])(=O)=O.[Na+].[Na+].CC(C)([O-])C.[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:19][C:20]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:21]=2[C:22](=[O:23])[NH:24][CH:25]([CH:27]2[CH2:29][CH2:28]2)[CH3:26])=[O:11])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Reactant: CCSC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
0.35 g of S-ethyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbothioate and 0.24 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide were dissolved in 5 ml of dimethyl sulfoxide, and 0.85 g of anhydrous sodium sulfate was added, followed by stirring for 5 minutes. 0.14 g of potassium tert-butoxide was added at room temperature, followed by stirring for 1.5 hours. The reaction liquid was added to water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.24 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[C:42]([O:51][CH3:52])[C:43]([O:49][CH3:50])=[CH:44][CH:45]=2)[O:40][C:39]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42]([O:51][CH3:52])[C:43]([O:49][CH3:50])=[CH:44][CH:45]=4)[O:40][C:39]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1OC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1OC
Yield: 41 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7,8-dimethoxy-2-phenyl-chromen-4-one (82 mg, 0.20 mmol) was reacted to give the title compound (41 mg, 41%). 1H NMR (400 MHz, CDCl3): δ 7.56-7.52 (d, 1H), 6.99-6.68 (m, 9H), 6.61-6.56 (d, 1H), 4.61-4.54 (m, 1H), 3.57-3.53 (m, 6H), 2.12-2.00 (m, 4H), 1.65-1.28 (m, 2H), 1.00-0.72 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]([NH2:31])=O)=[CH:5][CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]#[N:31])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)C(c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The reaction was carried out under argon. (rac)-7-(4-Cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide (10 mg, 24 μmol; prepared analogously to Example 72/73 from Example 70) was initially charged in dry THF (0.6 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 22 mg, 94 μmol, 4 eq.) was added and the mixture was stirred at RT for 1 h. HPLC showed complete conversion. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (8.3 mg, 87% of theory).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (9 mg, 31%), MS (ISP) m/z=402.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and butyric acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[CH2:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>COCCOC.[Cl-].[Na+].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>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[CH2:12])=[CH:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-vinyl]-quinoline (Example 154, 2.5 g, 8.15 mmol) was dissolved in DME (20 mL) under argon atm. 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.54 g, 12.22 mmol) was added, followed by 2 M K2CO3 (11 mL) and PdCl2(PPh3)2 (172 mg). The RM was stirred at 90° C. for 3 h. It was then taken into a mixture of EtOAc and brine and extracted. Organic phase was dried on Na2SO4. After evaporation of the solvent the crude was purified by column chromatography in silica gel with the eluent EtOAc/MeOH=9:1 then 4:1. The collected fractions containing product were concentrated and recrystallized from EtOAc/pentane. After a night drying under vacuo, the title compound was obtained as a beige powder (tR 3.65 min (conditions 3), MH+=353).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[C:15]1([CH2:21][CH2:22][CH2:23][Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][CH2:22][CH2:23][CH:4]2[C:5]3[NH:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:9]=3[CH2:2][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CCOC(=O)c1cc2c([nH]1)CCC2=O
Product: CCOC(=O)c1cc2c([nH]1)C(CCCc1ccccc1)CC2

Procedure:
The title compound was synthesized from ethyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol, 1 equiv) and 3-phenyl-propyl magnesium bromide (12.4 mL, 0.5M in THF, 6.2 mmol, 4 equiv) according to General Procedure 3 to give the exo olefin-containing compound (E)-ethyl 6-(3-phenylpropylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 with 5% Pd on carbon, and was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound (42.1 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (br. s., 1H), 7.28-7.33 (m, 2H), 7.16-7.23 (m, 3H), 6.64 (d, J=1.64 Hz, 1H), 4.25-4.34 (m, 2H), 3.00-3.09 (m, 1H), 2.51-2.68 (m, 5H), 1.97-2.07 (m, 1H), 1.65-1.77 (m, 3H), 1.47-1.55 (m, 1H), 1.34 (t, J=7.13 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH:27]=O)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.CO>C(O)(=O)C.C(Cl)(Cl)Cl>[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Reactant: C1COCCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
Morpholine (0.032 mL, 0.3699 mmol) was added to a stirred solution of 3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.3082 mmol) in acetic acid (2 mL) and stirred at room temperature for 4 hours. This was followed by the addition of NaBH (OAc)3 (98 mg, 0.4624 mmol). The resulting reaction mass was stirred at room temperature for 24 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was concentrated under reduced pressure, added ice, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 25 mg of the product (20.6% yield).