Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:11][C:12]([NH2:14])=[S:13]>CN(C)C=O>[ClH:2].[N:5]1([CH2:4][CH2:3][NH:14][C:12](=[NH:11])[SH:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCCCC1
Reactant: NC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(S)NCCN1CCCCC1
Temperature: 20 °C

Procedure:
2-(1-Piperidyl)ethylisothiourea hydrochloride was prepared in the following way: A suspension of 100 g of N-(2-chloroethyl) piperidine hydrochloride and of 41.5 g of thiourea in 250 cm3 of dimethylformamide was heated at a temperature in the region of 110° C. for 2 hours. The mixture was cooled to a temperature in the region of 20° C. The white solid formed was subsequently filtered off, rinsed with a total of 100 cm3 of diethyl ether and dried under reduced pressure (10 kPa) at a temperature in the region of 40° C. to result in 134.1 g of 2-(1-piperidyl)-ethylisothiourea hydrochloride in the form of a white solid that melted at a temperature in the region of 240° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)[N:19]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:32][C:27]1[CH:26]=[C:25]([CH2:24][N:20]2[C:21](=[O:23])[NH:22][C:18]([CH2:17][CH2:16][CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:33])=[O:3])=[CH:14][CH:13]=3)=[N:19]2)[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccc(C)c(C)c3)c(=O)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Cn2nc(CCCc3ccc(OC(C)(C)C(=O)O)cc3)[nH]c2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
2-(4-{3-[1-(3,4-Dimethylphenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methylpropionic acid ethyl ester (916 mg, 1.97 mmol) was dissolved in ethanol (10 mL) and 2N NaOH (3.0 mL, 6.0 mmol) was added in one portion. The solution was stirred at room temperature for one hour, then concentrated to a hazy colorless oil. This oil was partitioned between 1N HCl (10 mL) and ethyl acetate (10 mL). The aqueous layer was then reextracted with ethyl acetate (10 mL). Solids precipitated from this solution on stirring. The slurry was cooled to 0° C., filtered and dried in vacuo at 50° C. overnight to afford the title compound as a white solid (695 mg, 80%): mp 145.8-149.6° C.; 1H-NMR (DMSO-d6) δ 12.98 (s, 1H), 7.05 (dd, 3H, J=8.5, 3.0 Hz), 7.00 (s, 1H), 6.93 (d, 1H, J=7.5 Hz), 6.73 (d, 2H, J=8.5 Hz), 4.73 (s, 2H), 2.52 (t, 2H, J=7.5 Hz), 2.47 (t, 2H, J=7.5 Hz), 2.14 (s, 6H), 1.80 (quint, 2H, J=7.5 Hz), 1.46 (s, 6H); 13C NMR (DMSO-d6, 20° C.) δ 175.8, 154.1, 154.0, 147.1, 136.8, 135.9, 135.3, 135.2, 130.1, 129.7, 129.4, 125.7, 119.2, 78.9, 48.4, 34.1, 27.7, 27.6, 25.7, 25.1, 20.0, 19.7; IR (CHCl3) 2936, 2490, 1730, 1658, 1510, 1148 cm−1; Anal. Calcd. for C25H31N3O4: C, 68.63; H, 7.14; N, 9.60. Found: C, 68.23; H, 7.01; N, 9.44.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.[CH2:39]1[C@@H:42]([C:43]([OH:45])=[O:44])[NH:41][CH2:40]1>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:41]4[CH2:40][CH2:39][CH:42]4[C:43]([OH:45])=[O:44])[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: O=C(O)[C@@H]1CCN1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN2CCC2C(=O)O)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added L-azetidine-2-carboxylic acid (47 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 533 (M+H).
Reaction SMILES: [H-].[Na+].N#N.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=O.O.[CH3:29]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:29]
Reactant: O=CCCCCCCCCCCCCCCOC1CCCCO1
Reactant: CS(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A 300-ml three-necked flask equipped with a stirrer, dropping funnel and N2 inlet tube was charged with 40 ml of dimethyl sulfoxide and 1.2 g (30 mmol) of 60% sodium hydride. The contents were stirred at 75° C. for 1.5 hours in an N2 atmosphere and then cooled to room temperature. To this mixture, a solution of 8.93 g (25 mmol) of methyltriphenylphosphonium bromide in 40 ml of dimethyl sulfoxide was added dropwise over 10 minutes. The resultant mixture was stirred further for 20 minutes at room temperature. To this mixture, a solution of 3.27 g (10 mmol) of 15-(2-tetrahydropyranyloxy)pentadecanal in 15 ml of THF was added dropwise over 5 minutes, followed by stirring further for 30 minutes. After completion of the reaction, the reaction mixture was added with water and subjected to extraction with hexane, followed by concentration under reduced pressure. Thereafter, the resultant residue was purified by flash column chromatography on silica gel, thereby obtaining 1.49 g (yield: 46%) of 1-(2-tetrahydropyranyloxy)-15-hexadecene.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC1(COC(C)=O)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 72 h
Yield: 61.2 %

Procedure:
2.50 g. (8.82 mmoles) of 1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine are dissolved in 15 ml. of absolute pyridine. 15 ml. of acetic anhydride are added to the solution, and the mixture is allowed to stand at room temperature for three days. Thereafter the solution is evaporated in vacuo, and the oily residue is stirred with a 5% sodium hydrocarbonate solution. The separated solid substance is filtered off, washed with water, dried, and recrystallized first from aqueous methanol and then from methanol. 1.75 g. (61.2%) of the title compound are obtained in the form of shiny crystals melting at 96°-97° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(C)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(Cl)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.28 mmol) was added to a stirred solution of [6-chloro-3-methyl-4-(4-p-tolylsulfamoyl-phenyl)-naphthalen-2-yl]-acetic acid methyl ester (0.035 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded [6-chloro-3-methyl-4-(4-p-tolylsulfamoyl-phenyl)-naphthalen-2-yl]-acetic acid (0.03 g, 88%) as a solid. 1H NMR (DMSO-d6) δ: 12.48 (br. s, 1H), 10.09 (s, 1H), 7.77-8.05 (m, 4H), 7.33-7.56 (m, 3H), 6.95-7.16 (m, 4H), 6.82 (s, 1H), 3.84 (s, 2H), 2.21 (s, 3H), 2.02 (s, 3H). MS calcd. for C26H21ClNO4S [(M−H)−] 478, obsd. 478.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:27]([CH3:44])[NH:26][C:25]=1[CH:45]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:45]\[C:25]1[NH:26][C:27]([CH3:44])=[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol), 3,5-dimethyl-4-[3-oxo-3-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-propyl]-1H-pyrrole-2-carbaldehyde (1.7 eq.) and piperidine (1.5 eq.) in ethanol (2 mL) was stirred at rt for 96 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a pale orange solid.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15]CCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:70])([C:66]([F:69])([F:68])[F:67])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]C=C)[C:53]([O:55]CC)=[O:54]>>[CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:70])[C:66]([F:67])([F:68])[F:69])[C:53]([OH:55])=[O:54])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared in Example 5, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:12][C:13]#[N:14])=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:4]([F:28])[CH:3]=1.[OH2:29]>S(=O)(=O)(O)O>[C:13]([CH2:12][C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:28])=[C:5]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])[C:6]=2[O:10][C:9]=1[CH3:11])(=[O:29])[NH2:14]
Reactant: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2c1CC#N
Reactant: O
Agent: O=S(=O)(O)O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2c1CC(N)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
0.50 g (1.2 mmol) of 3-(4-chloro-3-cyanomethyl-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of 50% sulfuric acid, followed by stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.39 g (yield: 75%) of the desired product as white crystals. Melting point: 127-129° C.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Al](C)C.CCCCCC>ClCCl>[C:15]1([C@@H:21]([NH:23][C:4]([C:6]2[S:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[O:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nc2ccncc2s1
Reactant: C[C@H](N)c1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@H](NC(=O)c1nc2ccncc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1(S)-phenyl ethyl amine (0.03 mL, 0.23 mmol)in dichloromethane(0.3 mL) was added a solution of trimethylaluminum in hexane(0.115 mL, 2.0 M., 0.23 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 1:1)and triturated in hexane to give 12 mg of the thiazolo derivative.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:25][N:26]=[C:27]=[O:28]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:27]([NH:26][CH3:25])=[O:28])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NC(C)c1ccc(-c2nnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of Example 24G (0.044 g, 0.122 mmol) in CH2Cl2 (2 mL) was treated with methyl isocyanate (0.035 g, 0.61 mmol). The reaction was stirred at 25° C. for 1 hour and was concentrated under reduced pressure on a rotary evaporator. The residual white solids (0.046 g) were purified by flash chromatography on silica gel eluting with a solvent gradient from 50% to 70% ethyl acetate in hexanes to provide 0.025 g (49%) of the title compound as a white solid, 1H NMR (300 MHz, DMSO-d6) δ ppm 7.48 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.96 (dd, J=3.86, 0.92 Hz, 1H) 6.53 (d, J=8.09 Hz, 1H) 5.75 (q, J=4.78 Hz, 1H) 4.94-5.05 (m, 1H) 4.63 (heptet, J=5.88 Hz, 1H) 2.56 (d, J=4.78 Hz, 3H) 1.42 (d, J=6.99 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 419 (M+H+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C(OC([N:38]1[CH2:44][CH2:43][CH2:42][C@H:39]1[CH:40]=O)=O)(C)(C)C.[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][CH2:40][CH:39]2[CH2:42][CH2:43][CH2:44][NH:38]2)=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCC2CCCN2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.231 g, 0.58 mmol) in dry MeOH (5.5 mL) was added N-(tert-butoxycarbonyl)-L-prolinal (0.116 g, 0.58 mmol) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure and subjected to high vacuum for 1 h. The residue was dissolved in dry MeOH (5 mL) and to the resultant solution was added sodium borohydride (44 mg, 1.16 mmol), which was stirred for 0.5 h (see General Procedures XX). Purification by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 100:1:1 followed by 50:1:1) afforded the desired product (0.151 g, 45%) as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][C:12]([N:14]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[C:15]1[C:20]([S:21](O)(=[O:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:38]>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][C:12]([N:14]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[C:15]1[C:20]([S:21]([Cl:38])(=[O:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:13]
Reactant: COCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2ccccc2)cccc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2ccccc2)cccc1S(=O)(=O)Cl

Procedure:
To a solution of 3.8 g (7 mmol) of the N,N-diethylethanamine salt of 2-[(3-methoxy-1-oxopropyl)(trifluoroacetyl)amino][1,1'-biphenyl]-3-sulphonic acid in 14 ml of dichloromethane are added 1.75 g (8.4 mmol) of phosphorus pentachloride, the mixture is heated for 3 hours at the reflux temperature and is then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with dichloromethane.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[CH3:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:24]=[C:25]([NH:26][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccccc1Oc1cccc(N)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1Oc1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 28.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 61° and 65° C., to a solution of 3-(2-methylphenoxy)aniline (6 g) and triethylamine (6.1 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 35 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (400 cc). The solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 5 times with distilled water (500 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (7 g) is thereby obtained, which is dissolved in boiling acetonitrile (100 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and twice with diethyl ether (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-methylphenoxy)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.6 g), in the form of white crystals, m.p. 180° C. is thereby obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[CH:7][C:8](=O)[NH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([Cl:27])=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1n[nH]c(=O)cc1-c1ccc(OC2CCCCC2)cc1
Product: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C

Procedure:
A suspension of the pyridazin-3-one (58.4 mmol, 19.1 g) in phosphorous oxychloride (292 mmol, 26.7 mL) was heated at 90° C. for 30 min with stirring during which period the starting material was fully consumed as judged by TLC. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 (3×100 mL), brine (100 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge eluting with 0-10% ethyl acetate in hexanes to afford 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[S:3][C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=4)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=3[N:6]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(Br)cc3)sc2c1-c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (200 mg, 0.403 mmol), 4-bromophenylboronic acid (113 mg, 0.564 mmol), tetrakis(triphenylphosphine)palladium(0) (69.8 mg, 0.060 mmol), and K2CO3 (167 mg, 1.208 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (4 mL) and degassed water (1 mL). The reaction mixture was stirred at 75° C. for 5 h, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C28H28BrClNO3S (M+H+): 572.1 and 573.9; Found: 574.2 (M+H+).