Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][CH2:7][O:8][S:9](=[O:12])(=[O:11])[NH2:10])(=O)(=O)N.[CH2:13]([OH:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCO>>[S:9]([O:24][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:6][CH2:7][O:8][S:9](=[O:11])(=[O:12])[NH2:10])(=[O:11])(=[O:8])[NH2:10]
Reactant: OCCCCCCCCCCO
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Product: NS(=O)(=O)OCCCCCCCCCCOS(N)(=O)=O

Procedure:
1,10-Bis-O-sulfamyl-1,10-decanediol is prepared in the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in Example 1 except that 1,10-decanediol (67 g., 0.385 mol.) is employed as the alkanediol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C@H:9]([C:11](=[O:41])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:43]([OH:54])(=O)[C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:16]=3[N:15]([C:48](=[O:50])[C:47]3[CH:46]=[CH:45][C:44]([C:43]([N:15]4[C:16]5[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:41])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:42])[CH3:8])[CH3:10])[CH2:14]4)=[O:54])=[CH:52][CH:51]=3)[CH2:14][C@H:13]([NH:12][C:11](=[O:41])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:42])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.5 %

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-7-cyano-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 4) (120 mg, 0.189 mmol) in pyridine (2 mL) was added terephthalic acid (20.604 mg, 0.113 mmol). After 10 min, the mixture was cooled to 0° C., POCl3 (0.036 mL, 0.396 mmol) was added and the cooling bath was removed. After 1 h, the mixture was concentrated, the residue was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to provide tert-butyl N-[(1S)-2-[[(3S)-1-[(6-bromo-2-methoxy-1-naphthyl)methyl]-5-[4-[(3S)-1-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (6 mg, 1%) as an off white solid. LC-MS: 1403.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH3:42])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOC(C)=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (135 mg, 0.28 mmol) and ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (78 mg, 0.29 mmol) was added Et3 N (0.1 mL, 0.72 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed successively with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 160 mg(q.y.) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an oil. 1H-NMR (CDCl3) δ 1.13–1.23 (m, 3 H), 1.37–1.40 (m, 3 H), 2.90–3.89 (m, 12 H), 4.09–4.28 (m, 2 H), 4.33–4.39 (m, 2 H), 6.70–8.21 (series of m, total 12 H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([C:16]1([NH2:39])[C:22](=[O:23])[N:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]1=[O:38])=O)C>>[CH:1]1([CH2:6][C:7]([NH:39][C@H:16]([C:22]([NH:39][CH:16]2[C:17](=[O:38])[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[N:21]([CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:22]2=[O:23])=[O:23])[CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white amorphous solid. Purification was by flash chromatography eluting with CH2C2/EtOAc (2:1 gradient to 3:2). Rf=0.29 (CH2Cl2/EtOAc, 2:1).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:32][C:28]([F:33])([C:27]([F:35])([F:34])[F:26])[C:29]([O:31][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:30]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)C(F)(F)F)CCCCC1

Procedure:
1-Nitrosocyclohexyl 2,2,3,3,3-pentafluoropropanoate was prepared from cyclohexanone oxime, lead tetraacetate and pentafluoropropionic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 2.35-2.31 (2H, m), 1.77-2.00 (4H, m), 1.49-1.72 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[C:33]([CH2:35][CH2:36][N:37]([CH3:47])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)#[N:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([N:37]([CH2:36][CH2:35][C:33]#[N:34])[CH3:47])=[O:46])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(CCC#N)C(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)CCC#N)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-cyano-ethyl)-N-methyl-acetamide in an analogous manner as described in example 1. LR-MS: 653.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:2]([Cl:1])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCCCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.5 %

Procedure:
In a four necked round bottom flask, triphosgene (22.0 g, 74.2 mmol) was dissolved in toluene (325 mL) under argon. After cooling at 0° C., pyridine (19.2 mL, 237.5 mmol) was added dropwise during 1 h and the resulting suspension stirred for 1 h at 0° C. 5-phenylpentanol (25 mL, 148.4 mmol) was added drop wise in 30 min. After stirring at rt for 16 h the solid was filtered-off and the solvent removed under vacuum yielding the title compound (31.7 g, 94%), which was used in the next step without further purification. Rf=0.75 (Cy/AcOEt 8:2). FTIR (cm−1): 3087, 3063, 3027, 2936, 2859, 1778, 1744, 1604, 1496, 1455, 1382, 1260, 1146, 1031, 941, 835, 731, 696.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH2:13][C:14]#[C:15][CH2:16]O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Br)(Br)[Br:19]>C1(C)C=CC=CC=1>[Br:19][CH2:16][C:15]#[C:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC#CCc1ccccc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.5 ml of pyridine were added to a mixture of 140.4 g (0.96 mol) of 4-phenyl-2-butyn-1-ol (prepared according to G. Dupont, Bull. Soc. Chim. Fr., 1954, page 816) and 600 ml of dry toluene, after which 119.1 g (0.44 mol) of phosphorus tribromide were added dropwise in the course of 2 hours, the temperature not being allowed to exceed 50° C. The mixture was stirred overnight at room temperature and then poured onto 1,000 ml of ice water, the organic phase was separated off and the aqueous phase was extracted several times with methyl tert-butyl ether. The combined organic phases were then washed neutral and dried. The crude product obtained after the solvent had been stripped off under reduced pressure was subjected to fractional distillation. Yield: 126 g of product having a purity of 93% according to gas chromatography; bp.: 83°-85° C. at 0.3 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([OH:12])=O)[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.C(Cl)(=O)C(Cl)=O.[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[Cl:31])=[O:12])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Reactant: Nc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)Nc2ccccc2Cl)c1
Reaction time: 0.17 h

Procedure:
To a suspension of [5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (15 mg, 0.041 mmol) (see step 2 in Example 16) in DCM (0.5 mL) was added oxalyl chloride (58 mg, 0.454 mmol). This was followed by addition of DMF (1 drop) and then, following bubbling cessation, by addition of 2-chloroaniline (158 mg, 1.239 mmol). After 10 minutes, the reaction mixture was concentrated, taken up in DMF/MeOH and purified by reverse phase chromatography, eluting with 30-95% MeCN/H2O+0.1% TFA. The product fraction was lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.83 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.55 (m, 3H), 7.34 (m, 1H), 7.24 (m, 1H), 5.85 (s, 2H). HRMS (M+1)=472.0152.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:11][CH2:10][CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: OCCBr
Reactant: O=Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cnn(CCO)c1
Temperature: 150 °C

Procedure:
Combine 1H-pyrazole-4-carbaldehyde (0.110 g, 1.14 mmol), 2-bromoethanol (0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150° C. for 20 min. Cool to room temperature and filter, washing with acetonitrile. Concentrate filtrate to give the title preparation (0.155 g, 97%). GC-MS: m/z=140 [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[C:6]([CH3:8])[CH:7]=1.S(=O)(=O)(O)[OH:16]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[C:11](=[O:16])[C:10](=[O:14])[NH:9]2
Reactant: Cc1cc(C)cc(NC(=O)C=NO)c1
Reactant: O=S(=O)(O)O
Product: Cc1cc(C)c2c(c1)NC(=O)C2=O
Temperature: 80 °C

Procedure:
N-(3,5-Dimethyl-phenyl)-2-hydroxyimino-acetamide (13.7 g, 71.3 mmol) was added to concentrated sulfuric acid (70 mL) in a 250 mL flask. The reaction mixture was then heated at 80° C. for 30 minutes, then cooled to room temperature, and poured into ice-water (200 mL). The precipitated solid was filtered and washed with water (100 mL) and dried under vacuum to give 4,6-dimethyl-1H-indole-2,3-dione as an orange solid. Yield: 5.53 g (44%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](O)[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:21][CH:22]=1)(=[O:5])=[O:4]
Reactant: Oc1ccc2cccnc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Trifluoromethanesulfonic anhydride (1.40 mL, 8.32 mmol) was added dropwise via a syringe to a solution of quinolin-7-ol (930 mg, 6.41 mmol), and pyridine (1.05 mL, 13.0 mmol) in anhydrous dichloromethane (50 mL) at 0° C. After addition the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and purified via flash chromatography using an Analogix SF25-40 g column and eluant of ethyl acetate in heptane (0-40%) to afford the title compound as an orange-white solid (1.54 g, 86.7%). LC-MS m/z 278.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.57 (m, 2H) 7.95 (d, J=8.98 Hz, 1H) 8.05 (d, J=2.54 Hz, 1H) 8.20-8.29 (m, 1H) 8.97-9.06 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)=[C:5]2[CH2:19][CH2:20][N:21]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:37]([N:21]([CH2:20][CH2:19][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:46]([N:45]([CH3:49])[CH3:44])=[O:47])[CH:3]=2)[NH:7][C:6]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-{4-[4-({2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}benzylamino)butyl]phenyl}methanesulfonamide (15 mg in 1.5 mL of dry methylene chloride) at 0° C. was added dimethylcarbamyl chloride (0.03 mL of a 10% v/v solution in methylene chloride) and diisopropylethylamine (0.053 mL of a 10% v/v solution in methylene chloride) and the mixture warmed to room temperature. After 3 days the reaction was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) to give the title compound (17 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3cc[nH]c3c2)CC1
Yield: 129.5 %

Procedure:
In a similar manner to Step 1 of Reference Example 2, indole-6-carboxylic acid (200 mg, 1.24 mmol) was dissolved in DMF (2 mL), and the solution was treated with EDCI (475 mg, 2.48 mmol), HOBT monohydrate (168 mg, 1.24 mmol) and 1-(tert-butoxycarbonyl)piperazine (461 mg, 2.48 mmol) to obtain 6-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indole (529 mg).
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:4]=2[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:3][C:4]=2[CH:10]=1
Reactant: C1CCNC1
Reactant: Brc1ccc2[nH]c(Br)nc2c1
Solvent: CC#N
Product: Brc1ccc2[nH]c(N3CCCC3)nc2c1
Temperature: 150 °C

Procedure:
A suspension of 1 g (3.6 mmol) of 2,5-dibromo-1H-benzimidazole and 0.85 mL (10.18 mmol) of pyrrolidine in 45 mL of acetonitrile is heated for 2 hours at 150° C. in the microwave. The reaction mixture is poured onto water and extracted with EtOAc. The organic phase is washed three times with water and dried over sodium sulfate. The solvent is distilled off, and the residue is stirred with DIPE and the solid is filtered off. Yield: 0.43 g (45% of theoretical); C11H12BrN3 (M=266.13); calc.: molpeak (M−H)—: 264/266; found: molpeak (M−H)−: 264/266; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[OH:29][CH:30]([CH3:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O1CCCC1>[OH:29][CH:30]([CH3:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:38])=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: CC(=O)CCCCCCC(C)O
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=CCCCCC(=O)O)CCCCCCC(C)O
Yield: 98.3 %

Procedure:
325 g (0.7 mol) of (5-carboxypentyl)triphenylphosphonium bromide were dissolved in 1500 ml of tetrahydrofuran. After the addition of 180 g (1.6 mol) of potassium t-butylate in 700 ml of tetrahydrofuran the mixture was treated with 175 g (0.71 mol) of 9-hydroxy-2-decanone (70% purity). After usual work up 186 g of crude 14-hydroxy-7-methyl-pentadec-6-enoic acid were obtained. This product was dissolved in 400 ml of methanol and, after the addition of 5 ml of concentrated sulphuric acid, heated to reflux for 2 hours. After work up, bulb-tube distillation and chromatography 102 g (50%) of methyl 14-hydroxy-7-methyl- pentadec-6-enoate were obtained having the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=2)[N:21]=1>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[CH:27]=[CH:28][C:29]([C:30]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:7]=3)=[CH:32][CH:33]=2)[N:21]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: N#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2nc(-c3ccc(F)cc3)no2)cc1
Temperature: 100 °C
Yield: 17.8 %

Procedure:
To a solution of 4-fluoro-N′-hydroxybenzimidamide (Intermediate-18, 0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere was added 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (step-4 of Intermediate-17, 0.100 g, 0.31 mmol) and ZnCl2 (0.0087 g, 0.06 mmol). The reaction mass was heated at 100° C. for 8-10 h. The reaction mass was quenched with water, extracted in DCM and column purified to afford 0.025 g of desired product. 1H NMR (DMSO-d6): δ 7.02 (br s, 1H), 7.33 (t, 1H), 7.45-7.54 (m, 2H), 7.61 (d, 1H), 7.70 (m, 1H), 7.83 (t, 1H), 8.09-8.17 (m, 2H), 8.26-8.30 (m, 2H), 12.81 (br s, 1H). MS (m/z): 452.05 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:21][CH2:20][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37].Cl>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:10][CH2:11][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[N:13]3[C:36]([C:32]3[NH:31][CH:35]=[CH:34][CH:33]=3)=[O:37])[CH2:20][CH2:21]2)=[CH:22][CH:23]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Reactant: O=C(Cl)c1ccc[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.5 %

Procedure:
In 6 ml of methylene chloride were dissolved 0.30 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 0.47 ml of triethylamine. After adding 0.18 g of 1H-2-pyrrolecarbonyl chloride at 0-5° C., the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After purifying the residue by column chromatography [eluent: chloroform:ethanol=200:1], isopropyl ether was added and the deposited crystal was collected by filtration. Thus, 0.14 g of (3R)-8-(4-isopropylphenoxy)-4-(1H-2-pyrrolylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid was obtained as a yellow crystalline product.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:34]
Reactant: CSc1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a stirred solution of 2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.22 g, 0.58 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.30 g, 1.5 mmol) in DCM (3 mL). The mixture was stirred at 0° C. for 2 h. The mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.22 g, 96%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.12-8.14 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.50 (dd, J=8.7, 1.2 Hz, 1H), 7.37 (t, J=8.4 Hz, 2H), 5.57 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/z 396 (M+H)+.