Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:9])=[CH:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[Cl:1][C:2]([Cl:9])=[CH:3][CH2:4][CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=C(O)CCC=C(Cl)Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCC=C(Cl)Cl
Yield: 90.3 %

Procedure:
152 g of the 4,4-dichlorobut-3-ene-1-carboxylic acid is stirred with 140 g of thionyl chloride for 2 hours. The subsequent distillation yields 152.3 g of 4,4-dichlorobut-3-ene-1-carboxylic acid chloride; b.p. 62° C./15 Torr [b.p. 64°-65° C./11 Torr according to J. Ray and R. Vessiere, Bull. Soc. Chim. France, 269 (1967)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: Cc1ccn(-c2cccc(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-chlorophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+: calc. 467.094465; found 467.091517.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])([F:6])[F:5].C(N(CC)CC)C.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:22]([O:1][CH2:2][CH2:3][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])([F:6])[F:5])([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CCOP(=O)(OCC)C(F)(F)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Diethyl 3-hydroxy-1,1-difluoro-propylphosphonate [1225194-19-3] (4.4 g, 0.019 mol) was dissolved in CH2Cl2 (20 mL) and triethylamine (7.7 g) and treated with TsCl (5.4 g, 0.029 mol) followed by DMAP (0.23 g, 0.0019 mol) at rt for 2 h. After 2 h, an additional portion of TsCl (0.6 g) was added. After 30 m, the reaction mixture was partitioned between water and CH2Cl2. The organic layer was filtered and concentrated in vacuo. The residue was dissolved in 1:1 hexanes:CH2Cl2 (100 mL) and applied to 85 g flash silica gel (topped with Na2SO4 and equilibrated with hexanes). The column was eluted with hexanes-ethyl acetate. Intermediate 23 weighed 6.3 g (94%). 1H NMR (CDCl3) 7.2-7.8 (AB, 4H); 3.9-4.4 (m, 6H); 2.0-3.0 (m, 5H), 1.4 (t, 6H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:46][CH:47]=2)[CH2:36][CH2:37]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CN1CCN(CCCNc2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NCCCN4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (prepared below, 86.2 mg, 0.347 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and then diluted with Hexanes (˜40 mL). The black precipitate that formed was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was dissolved in EtOAc (˜5 mL) and triturated with Hexane (˜50 mL) to give a yellow precipitate. The precipitate was filtered and washed with 0° C. i-prOH (˜5 mL) yielding 51% (0.0802 g, 0.127 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18](O)=[O:19])=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:28][CH:27]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:19][N:36]=[C:25]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([NH2:33])(=[O:34])=[O:35])=[CH:30][CH:31]=5)[N:24]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)cc1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (heptane/diethyl ether) as an off-white solid (186 mg, 77%). MS (ISP) 486.3 [(M+H)+]; mp 288° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[C:6]([Cl:17])[N:5]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[Cl:17][C:6]1[CH:7]=[C:8]([N:10]([CH3:18])[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:9]=[C:4]([Cl:3])[N:5]=1
Reactant: CI
Reactant: Clc1cc(Nc2cncnc2)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
NaH (103 mg, 4.29 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (9.5 mL) was added. The slurry was cooled to 0° C. and compound 13 (938 mg, 3.89 mmol, 1.00 eq) was added as a solution in THF (9.5 mL). After stirring at 0° C. for 30 minutes methyl iodide (267 μL, 4.29 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 920 mg (93%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.87 (s, 2H), 6.77 (s, 2H), 3.36 (s, 3H); [M+1]+: 255.0.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[C@@H:16]([C:17]#[N:18])[NH:15][C:14]1=[O:19].C(N(CC)CC)C.Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][C:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])([CH3:46])[CH3:45])[C:39](Cl)=[O:40])[N:37]=1)=[O:31]>O1CCCC1>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][C:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=2)=[O:48])([CH3:45])[CH3:46])[C:39]([NH:12][C@H:13]2[C@@H:16]([C:17]#[N:18])[NH:15][C:14]2=[O:19])=[O:40])[N:37]=1)=[O:31]
Reactant: N#C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(ON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
In 12 ml of tetrahydrofuran was dissolved 0.30 g of (3S, 4S)-3-amino-4-cyano-2-azetidinone p-toluenesulfonate. To the solution were added, under ice-cooling, 0.12 g of triethylamine and, subsequently 0.60 g of 2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was purified on a silicagel column [ethyl acetate-chloroformmethanol (3:3:1)] to yield 0.27 g of (3S, 4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:10]1[C:9]2[C:4](=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: Cc1nc2c([N+](=O)[O-])cccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Yield: 55 %

Procedure:
To a solution of 2-methyl-8-nitroquinazolin-4(3H)-one (250 mg, 1.22 mmol) in toluene (1 mL) was added POCl3 (374 mg, 2.44 mmol) and the reaction mixture was heated at reflux for 10 h. Then the reaction mixture was concentrated and triturated with Et2O. The precipitate obtained was filtered and dried to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.60-8.58 (d, J=7.8 Hz, 1H), 8.52-8.49 (d, J=9.0 Hz, 1H), 7.95-7.89 (t, J=7.8 Hz, 1H), 2.75 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([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[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([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][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) in dichloromethane (1.6 ml) was added at room temperature triethylamine (139 mg, 192 μl, 1.38 mmol) and methanesulfonyl chloride (43.0 mg, 29.2 μl, 375 μmol). The mixture was allowed to stir at room temperature for 4 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (0.1 g) was triturated with dichloromethane (1 ml) and heptane (5 mL) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (90 mg, 88%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Mg].[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)=[O:7].[Cl-].[NH4+]>O1CCCC1>[OH:7][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCBr
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
To a stirred and refluxed Grignard complex previously prepared starting from 55.1 parts of 1-bromopropane, 10.9 parts of magnesium and tetrahydrofuran was added a solution of 25 parts of N-(4-formylphenyl)acetamide in 225 parts of dry tetrahydrofuran. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water and a saturated ammonium chloride solution. The organic layer was decanted (and set aside) and the remaining phase was extracted with ethyl acetate. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 20 parts (64.3%) of N-[4-(1-hydroxybutyl)phenyl]acetamide as a residue (interm. 7).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.[C:15](OC(=O)C)(=O)C.N1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:5]([CH2:4][C:1](=[O:3])[CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1cccc(F)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Cc1cccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
2-Carboxymethyl-6-fluoro-benzoic acid (11.16 g, 56.32 mmol) in acetic anhydride (65 mL, 690 mmol) was heated at 110° C. for 60 minutes. Pyridine (20 mL, 250 mmol) was added. Gas evolution was observed. The reaction mixture was refluxed overnight and rotovaped. The residue was dissolved in tetrahydrofuran (100 mL) and 4 M aq. NaOH (100 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with conc. HCl (aq). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine, dried over MgSO4 and rotavaped. 20 mL toluene was added and the mixture was rotovaped to give crude 2-Fluoro-6-(2-oxo-propyl)-benzoic acid (12.3 g, yield 55.7%, purity ca. 50%). The purity was estimated by 1H NMR and the crude product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)c1
Reaction time: 22 h
Yield: 51.2 %

Procedure:
About 3 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (20 mg, 0.09 mmol) and 1-phenylpiperazine (13.4, 0.09 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (56 mg, 0.26 mmol) and molecular sieves (5 beads). After the reaction was carried out for about 22 hr, the reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution saturated sodium chloride solution. After drying the organic layer over anhydrous MgSO4, the solvent was removed under reduced pressure. After dissolving the residue with 1 mL of diethyl ether, HCl ether solution was slowly dropped to precipitate a white hydrochloric acid salt which was collected by filtration or centrifugation, and it was washed several times with diethyl ether. After drying the same under reduced pressure, was obtained 18.1 mg (56.8%) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[O:26][C:27]([CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[NH:40][CH:41]2[CH2:46][CH2:45][N:44]([C@@H:47]3[CH2:52][CH2:51][NH:50][C@@H:49]([CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:48]3)[CH2:43][CH2:42]2)=[CH:28][N:29]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([N:50]1[CH2:51][CH2:52][C@@H:47]([N:44]2[CH2:43][CH2:42][CH:41]([NH:40][C:32]3[N:31]([CH2:30][C:27]4[O:26][C:25]([CH3:24])=[N:29][CH:28]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:46][CH2:45]2)[CH2:48][C@@H:49]1[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:13]
Reactant: Cc1ncc(Cn2c(NC3CCN([C@@H]4CCN[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(Cn2c(NC3CCN([C@@H]4CCN(C(=O)c5oc6ccccc6c5C)[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Yield: 45.2 %

Procedure:
3-methyl-2-benzofurancarboxylic acid (0.100 g) and 1-hydroxy-1H-benzotriazole (0.070 g) were added to (±)-trans-1-[(2-methyl-5-oxazolyl)methyl]-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-1H-benzimidazol-2-amine (0.100 g) in CH2Cl2 (5 ml). The mixture was stirred under N2 atmosphere. A solution of triethylamine (0.5 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1:1) (0.080 g) in CH2Cl2 (10 ml) was added dropwise and the reaction mixture was stirred overnight at RT, under N2. Then, the compound was isolated and purified by column chromatography (eluent gradient: (0.5% ammoniumacetate in H2O)/CH3OH/CH3CN 70/15/15 upgrading over 0/50/50 to 0/0/100). The desired fractions were collected and the solvent was evaporated, yielding 0.060 g of (±)-trans-1-[(3-methyl-2-benzofuranyl)-carbonyl]-4-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-(phenylmethyl)piperidine.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:37]4[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (120 mg), acetic acid (0.023 mL) and sodium acetate (32.7 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (92 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (169 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D87) (126 mg). The crude product was used for next step without further purification. MS (ES): C27H29N3O3S requires 475. found 476.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][CH:6]=2)[N:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1nc(-c2ccccc2)cs1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Temperature: 25 °C

Procedure:
N-(4-Phenyl-thiazol-2-yl)-acetamide was added to chlorosulfonic acid (5 eq) at 0° C. and allowed to warm to room temperature. The mixture was heated at 70° C. for 1 h and carefully poured into ice. The solid was filtered, washed with water and dried under vacuum to give 4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl chloride. Characterized by derivatization as N-[4-(4-Isobutylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide, 1H NMR (400 MHz, CD3OD) 8.08 (d, 2H), 7.85 (d, 2H), 7.58 (s, 1H), 2.66 (d, 2H), 2.22 (s, 3H), 1.7 (m, 1H), 0.87 (d, 6H). LCMS (m/z): 354.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Temperature: 60 °C
Reaction time: 60 h
Yield: 24 %

Procedure:
To a solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1 eq), 4-hydroxybenzoic acid (1.1 eq), N-methylmorpholine (3 eq) in dry DMF (0.16 M), was added PyBop (1.5 eq). The reaction mixture was heated at 60° C. with stirring for 60 h. At this time the reaction was allowed to cool to RT partitioned between EtOAc and 1N aqueous HCl. The aqueous fraction was extracted with EtOAc and the combined organics washed with saturated aqueous Na2CO3, brine, before being dried over Na2SO4, filtered and evaporated in vacuo. Purification was by flash chromatography on silica gel (4:6) EtOAc/PE) to afford the title compound (24%).
Reaction SMILES: [C:1]1([CH:7]([NH:11]C(=O)OC(C)(C)C)[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH:7]([NH2:11])[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCC(NC(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 1.03 g of tert-butyl 1-phenylbut-3-ynylcarbamate (Formula 16) in 15 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. Then, dichloromethane was removed. The residue was diluted with water and extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (60% ethyl acetate/hexane) gave 564 mg (93%) of 1-phenylbut-3-yn-1-amine (Formula 17) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 2.04-2.05 (m, 1H), 2.43-2.63 (m, 2H), 4.14-4.19 (m, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[N:7]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(CNc2cncc(Cl)n2)cc1
Reactant: c1c[nH]cn1
Product: Fc1ccc(CNc2cncc(-n3ccnc3)n2)cc1
Yield: 77.2 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-(4-fluorobenzyl)pyrazin-2-amine (240 mg, 1.01 mmol) and imidazole (76 mg, 1.11 mmol) furnished the product (210 mg, 65%).