Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([N:5]=[C:1]=[O:2])[S:7][C:8]=2[CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2ccc(Cl)cc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-6-chlorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about 1 hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 6-chlorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:16]1=[O:24])([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: O=C1Cc2ccccc2N1
Product: COc1cc(C)c(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 2-oxindole to give 0.25 g of 3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].CO.C([BH3-])#[N:13].[Na+].[OH-].[Na+]>N.C(O)(=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([NH2:13])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cccnc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
3-Acetylpyridine (2.4 g, 20 mmol, Aldrich) was dissolved in 2M ammonia solution in methyl alcohol (50 mL, 100 mmol, Aldrich) and acetic acid (15 mL, J. T. Baker) was slowly added at 0 C. After stirring for 3 h at room temperature, the sodium cyanoborohydride (5.0 g, 80 mmol, Aldrich) was added to the solution at 0 C. The mixture was stirred under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with aqueous 5 N sodium hydroxide (30 mL, 150 mmol, J. T. Baker). The methyl alcohol was removed from the mixture via vacuo. The residue was extracted by diethyl ether (30 mL×4). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated via vacuo to give crude 1-pyridin-3-yl-ethylamine as light yellow oil in 44% yield (1.07 g, 8.8 mmol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl.[NH2:44][CH2:45][CH2:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:48]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH2:37][NH:44][CH2:45][CH2:46][C:47](=[O:48])[N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCC(=O)N1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield following steps 5 and 6, using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 3-amino-1-(pyrrolidin-1-yl)propan-1-one hydrochloride as the reactant amine MS: m/e 687.5 (MH+), 1.74 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3H) 0.98 (s, 3H) 1.02 (s, 3H) 1.08 (s, 3H) 1.16 (s, 3H) 1.73 (s, 3H) 0.90-1.86 (m, 20H) 1.88-1.96 (m, J=6.78, 6.78, 6.65, 6.40 Hz, 2H) 1.97-2.10 (m, 1H) 2.01 (dt, J=13.74, 6.81 Hz, 2H) 2.16 (dd, J=17.19, 6.40 Hz, 1H) 2.47-2.57 (m, 1H) 2.81 (t, J=6.02 Hz, 2H) 2.88 (d, J=12.55 Hz, 1H) 3.33-3.42 (m, 3H) 3.42-3.52 (m, 4H) 4.65 (s, 1H) 4.76 (d, J=1.76 Hz, 1H) 5.35 (dd, J=5.77, 1.00 Hz, 1H) 6.94 (d, J=11.80 Hz, 1H) 7.02 (dd, J=8.03, 1.25 Hz, 1H) 7.83 (t, J=7.91 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −112.76 (s, 1 F).
Reaction SMILES: CC1N=C2NC(=O)NC2=CC=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[NH:29][C:28](=[O:30])[NH:27][C:23]3=[N:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1.[CH2:31]([S:35](Cl)(=[O:37])=[O:36])CCC>>[CH3:31][S:35]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[NH:29][C:28](=[O:30])[NH:27][C:23]3=[N:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)(=[O:37])=[O:36]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Agent: Cc1ccc2[nH]c(=O)[nH]c2n1
Agent: Cl
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(NS(C)(=O)=O)cc1

Procedure:
Example 10 6-4-(Butanesulfonylamino)phenyl]-1,3-dihydro-5-methyl2H-imidazo[4,5-b]pyridin-2-one [I; Ar =4-CH3 (CH2)3SO2NHC6H4, R1 and R3 =H, R5 =CH3 ]was prepared from 1.5 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one hydrochloride and 0.91 ml butanesulfonyl chloride according to the procedure of Example 7, and was obtained (0.92 g) as a colorless solid, m.p. above 300° C. when recrystallized from ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][CH2:16][C:17]([N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].ClC1C(C)=C(C)N=C(C2C=CC=CC=2)N=1.NCC(N(CCC)CCC)=O>>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:15][CH2:16][C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH:7]=1
Reactant: Cc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CN(C(=O)CN)c1ccccc1
Agent: CCCN(CCC)C(=O)CN
Agent: Cc1nc(-c2ccccc2)nc(Cl)c1C
Product: Cc1cc(NCC(=O)N(C)c2ccccc2)nc(-c2ccccc2)n1

Procedure:
The same procedures as Example 1 are repeated except that 4-chloro-6-methyl-2-phenylpyrimidine and 2-amino-N-methyl-N-phenylacetamide are used instead of 4-chloro-5,6-dimethyl-2-phenylpyrimidine and 2-amino-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from isopropanol to give the desired compound, m.p. 134-136° C.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:13][CH:12]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:11]([C:19]([OH:21])=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C=O)C>[C:1]1([CH:7]([N:9]2[CH2:13][CH:12]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:11]([C:19]([Cl:25])=[O:21])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CC(C(=O)O)C(c2ccsc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(c1ccccc1)N1CC(C(=O)Cl)C(c2ccsc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The product from step c) (1064 mg, 3.53 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0° C. under N2 atmosphere and oxalyl chloride (1345 mg, 10.59 mmol) was added, followed by 2 drops of DMF. The reaction was stirred at 0° C. for 15 minutes and was allowed to come to room temperature. The reaction mixture was stirred for 1.5 hours and was evaporated to dryness to give the subtitle compound as a solid. MS calculated for C17H18ClNOS +H: 320, observed as methyl ester [dissolved in methanol]+H: 316.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][NH:17][C:18]4[C:23]([NH2:24])=[CH:22][N:21]=[CH:20][N:19]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:25][CH2:26][CH2:27][CH2:28][C@H:4]2[O:3]1.Br[C:31]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:21]1[CH:22]=[C:23]2[C:18]([N:17]([CH2:16][C:14]3[CH:13]=[CH:12][C:10]4[N:11]=[C:7]([N:6]5[C@@H:5]6[CH2:25][CH2:26][CH2:27][CH2:28][C@H:4]6[O:3][C:2]5([CH3:29])[CH3:1])[S:8][C:9]=4[CH:15]=3)[CH:31]=[N:24]2)=[N:19][CH:20]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncncc3N)cc2s1
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cncnc43)cc2s1

Procedure:
(3aR,7aR)-3-(6-((9H-Purin-9-yl)methyl)benzo[d]thiazol-2-yl)-2,2-dimethyloctahydrobenzo[d]oxazole was synthesized as an oil (220 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N4-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)pyrimidine-4,5-diamine from Step 6 of this Example for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1ccccc1Cl
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 82.6 %

Procedure:
To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2 mmol) in 25 mL of anhydrous DMF was added potassium carbonate (3.09 g, 22.4 mmol), followed by 2-chlorobenzaldehyde (1.26 mL, 11.3 mmol). The mixture was then heated under nitrogen atmosphere at 70° C. for 5 hours. The reaction mixture was then allowed to cool to room temperature and partitioned between ether and water. The aqueous layer was extracted with ether once and the combined organic layer was washed with water and brine, dried over sodium sulfate and condensed in vacuo. The crude product was purified via silica gel flash chromatography, eluting with 5-10% ether/hexanes, to give 2.62 g (9.25 mmol, 83%) of the desired aldehyde as a colorless oil, which solidified slowly upon standing at room temperature.
Reaction SMILES: [N:1]1([C@H:5]2[CH2:8][C@H:7]([C:9]3[S:10][C:11]4[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.BrC1C=CC2N=C([C@H]3[CH2:30][C@H:29]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH3:36])C3)SC=2C=1.CC1C(B2OC(C)(C)C(C)(C)O2)=CC=C(C)N=1.N1C=C(B(O)O)C=NC=1>>[N:1]1([C@H:5]2[CH2:8][C@H:7]([C:9]3[S:10][C:11]4[CH:17]=[C:16]([C:35]5[C:29]([CH3:30])=[N:31][C:32]([CH3:36])=[CH:33][CH:34]=5)[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCC4)C3)sc2c1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting Example 2A (2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine) for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.01 (d, J=8.48 Hz, 1H) 7.75 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.39 (dd, J=8.48, 1.70 Hz, 1H) 7.06 (d, J=7.80 Hz, 1H) 3.96-4.08 (m, 1H) 3.19-3.40 (m, 5H) 2.59 (s, 3H) 2.49 (s, 3H) 2.37-2.56 (m, 4H) 2.07-2.19 (m, 2H). MS: (M+H)+=350.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[C:27]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:25]=[C:24]([CH3:34])[N:23]=1>>[CH3:21][C:22]1[C:27]([N:28]2[CH2:33][CH2:32][N:31]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:20])=[CH:8][C:9]=3[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:30][CH2:29]2)=[CH:26][CH:25]=[C:24]([CH3:34])[N:23]=1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)n1
Yield: 35 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (189 mg) described in Preparation Example 22 and 1-(2,6-dimethylpyridin-3-yl)piperazine (113 mg) described in Preparation Example 94 and by the reaction and treatment in the same manner as in Example 87, the title compound (102 mg) was obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.[Na].[SH:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.O>COCCOC>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[S:29][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)[C:12]#[N:13]
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: [Na]
Solvent: COCCOC
Solvent: O
Product: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
1.517 g of O-[p-toluenesulfonyl)-m-phenoxymandelonitrile was dissolved in 5 ml of DME, and the solution was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (760 mg) was added, and the mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 1.5 hours. Water (20 ml) was added to the reaction mixture, and it was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 1.233 g (yield 85%) of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:15]([OH:23])[C:8]=2[S:9][C:10]=1[NH:11]C(=O)C)=[O:5])[CH3:2].OS(O)(=O)=O>CO.CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:15]([OH:23])[C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCCCc1cc(O)c2sc(NC(C)=O)c(C(=O)OCC)c2c1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CO
Product: CCCCc1cc(O)c2sc(N)c(C(=O)OCC)c2c1
Reaction time: 168 h

Procedure:
Compound 03-6 (3.64 g, 10.9 mmol) was suspended in a mixture of MeOH (450 mL) and MeCN (100 mL). H2SO4 (1.5 mL) was added and the mixture was stirred under a N2-atmosphere, while monitoring the reaction by HPLC. After 7 days the conversion was complete and the mixture was concentrated to half of the original volume. Water was added and the pH was cautiously adjusted to 8 with conc. NH4OH. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the crude product as a green sticky oil, which was purified by column chromatography (SiO2, EtOAc/Hept=1/4+1% Et3N). The product fractions were pooled and the solvent was removed in vacuo. The residue was dissolved in Et2O (50 mL) and the solution was washed with conc. aq. NH4Cl (2×50 mL) and brine (50 mL) to remove residual NEt3. After drying over Na2SO4, the solvent was removed in vacuo to give a-3 (2.6 g, 8.9 mmol, 82%) as a greenish grey solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)cc(C)c1
Product: CCOC(=O)c1cc(C)cc(CBr)c1

Procedure:
The subtitle compound was prepared from ethyl 3,5-dimethylbenzoate (2 g) and N-bromosuccinimide (2 g) by the method of example 5 step (i). Purification was by chromatography eluting with 5% ethyl acetate in isohexane Yield 1.85 g.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:45]=[C:44]([O:46][CH3:47])[C:38]2[O:39][CH2:40][CH2:41][CH2:42][O:43][C:37]=2[C:36]=1[F:48])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:48][C:36]1[C:37]2[O:43][CH2:42][CH2:41][CH2:40][O:39][C:38]=2[C:44]([O:46][CH3:47])=[CH:45][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
After adding 20 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 103 mg of [2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (67 mg) as a light brown solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: CC(=O)Nc1ccc(N=C=S)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(NC(=S)Nc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture containing 1.92 g of 4-acetamidophenylisothiocyanate and 1.62 g of 7-amino-3,4-dihydro-2(1H)quinolone in 10 ml of DMF was stirred for 6 h at 20° C. Water was added and the product filtered and washed with water. Yield 85%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][C:51]=1[NH:52][C:53](OC1C=CC([N+]([O-])=O)=CC=1)=[O:54])[C:45]([O:47][CH3:48])=[O:46].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:53]([NH:52][C:51]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=2[Cl:41])=[O:54])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(Cl)c1
Reaction time: 8 h
Yield: 131.8 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine in 3.0 mL of THF was added 171 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 352 mg of methyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 656
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[CH3:30][C@@H:31]1[C@H:35]([OH:36])[CH2:34][CH2:33][NH:32]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@@H:35]([OH:36])[C@H:31]3[CH3:30])[CH2:26][CH2:27]2)=[O:21])[CH2:3][CH2:2]1
Reactant: C[C@H]1NCC[C@H]1O
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@@H](O)[C@H]2C)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (2R,3R)-2-methyl-pyrrolidin-3-ol hydrochloride (example 188A) in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added 3-Bromomethyl-4,6-dimethyl-benzo[d]isothiazole, CAS: 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (69.5 mg, 0.27 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (45 mg, 55%) as colorless foam.