Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:17])=[N:14][O:15][N:16]=1)[CH3:2].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[C:11]2[N:3]([CH2:1][CH3:2])[C:4]([C:12]3[C:13]([NH2:17])=[N:14][O:15][N:16]=3)=[N:5][C:6]=2[CH:7]=[N:8][CH:9]=1
Reactant: CCn1c(-c2nonc2N)nc2cnccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Temperature: 100 °C
Yield: 34.3 %

Procedure:
To a solution of the product of Example 1 Step 1 (3.0 g, 17.9 mmol) in acetic acid (40 ml) was added bromine (3.12 g, 1 ml, 19.7 mmol) and the mixture was heated at 100° C. for 20 hours. After cooling the solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was washed with water (×3), dried and evaporated in vacuo. Purification of the residue by silica gel chromatography eluting with 50% dichloromethane in ethyl acetate afforded the title compound (1.9 g, 43%). 1H NMR (DMSO-d6) 8.73 (1H, s), 8.52 (1H, s), 7.0 (1H, br), 3.25 (2H, m), 1.16 (3H, t, J=7.2 Hz).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.C(=O)([O-])[O-:16].[Cs+].[Cs+].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1F)[C:25]#[N:26].C(OCC)(=O)C>C(#N)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[C:10]([C:11]([F:14])([F:12])[F:13])=[N:9]1)[C:25]([NH2:26])=[O:16]
Reactant: FC(F)(F)c1n[nH]c2nccc(I)c12
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(Cl)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
Compound (153a) (5.0 g), cesium carbonate (7.82 g), and 3-chloro-4-fluorobenzonitrile (3.0 g) were suspended in acetonitrile (50 mL), followed by stirring at 70° C. for 24 hr. The reaction solution was distributed between ethyl acetate and an aqueous ammonium chloride solution, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. Ethanol was added to the residue, and the precipitate was collected by filtration to obtain 3-chloro-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (4.77 g, 66%). 3-Chloro-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (2.53 g) was dissolved in DMSO (28 mL). A hydrogen peroxide solution (30 wt %) (0.700 mL) and a 4 mol % aqueous sodium hydroxide solution (1.41 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (153b) (2.26 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:21][CH2:18][CH2:19][S:20]2)=[C:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: Cc1c(Cl)nnc(C(=O)c2ccccc2)c1C
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(Cl)nnc(C2(c3ccccc3)SCCS2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a DCM solution of (6-chloro-4,5-dimethyl-pyridazin-3-yl)-phenyl-methanone (300 mg, 1.22 mmol) is added 1,2-ethandithiol (0.408 ml, 4.86 mmol) and BF3.OEt2 (0.154 ml, 1.216 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 16 h. The reaction was charged with BF3.OEt2 (0.154 ml, 1.216 mmol) and 1,2-ethandithiol (0.408 ml, 4.86 mmol), and heated at 40° C. for 6 h. The reaction is quenched with sat. NaHCO3 at 0° C. and organic phase is washed with brine. The organic layer is dried over Na2SO4, filtered and concentrated to afford a yellow solid. The residue is loaded on silica gel and purified by flash chromatography, eluting with 20-80% EtOAc: heptane. Fractions containing the desired product are combined and concentrated to afford a white solid (280 mg, 73%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[C:10]3[CH:23]=[CH:24][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:8][C:9]=3[S:13](=[O:15])(=[O:14])[N:12]=2)=[CH:17][CH:18]=1
Reactant: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCBr)cc21
Reactant: C1CCNCC1
Product: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCN3CCCCC3)cc21

Procedure:
According to the method in example 10, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxide and Piperidine were converted to yield 3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole 1,1-dioxide, MS: 433 (MH+, 1Cl).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([C:17]([N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4[N:36]=[C:37]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[O:38][C:39]=4[C:40]([F:43])([F:42])[F:41])=[O:34])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:44]1([C:37]2[O:38][C:39]([C:40]([F:41])([F:42])[F:43])=[C:35]([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([N:22]4[CH2:23][CH2:24][CH2:25][N:19]([C:17]([CH:14]5[CH2:13][CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:16][CH2:15]5)=[O:18])[CH2:20][CH2:21]4)=[CH:27][CH:28]=3)=[O:34])[N:36]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(N2CCCN(C(=O)[C@H]3CC[C@@H](C(=O)OCc4ccccc4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(N2CCCN(C(=O)C3CCC(C(=O)O)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reaction time: 3 h
Yield: 38.5 %

Procedure:
Cis-4-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (90 mg) was diluted in 30 mL of methanol and 100 mg of Pd/C (10%) was added. The mixture was placed on a Parr shaker for hydrogenation at 50 psi for 3 hr. The mixture was filtered and the solvent was removed to afford the product 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carbonyl)-cyclohexanecarboxylic acid (30 mg, 40% yield) as a white solid. LCMS for C30H31F3N4O5 calcd. (m/e) 584, observed 585 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=O)=[N:4]1)[CH3:2].C[N:13]([CH3:16])C=O.C(Cl)(=O)[C:18](Cl)=[O:19]>ClCCl>[CH3:18][O:19][N:13]([CH3:16])[C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[N:3]([CH2:1][CH3:2])[N:4]=1)=[O:11]
Reactant: CCn1nc(C(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCn1nc(C(=O)N(C)OC)cc1C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
1-Ethyl-5-methylpyrazole-3-carboxylic acid (5.25 g) in dry dichloromethane (100 ml) containing N,N-dimethylformamide (0.26 ml) was cooled in an ice-bath and treated with a solution of oxalyl chloride (3.27 ml) in dichloromethane (25 ml), added dropwise. The mixture was stirred in the cold for 25 min, and then allowed to warm to room temperature, when evolution of a gas was observed. After 10 min the solvent was removed by evaporation in vacuo and toluene was added and removed (×2) to ensure any residual HCl and oxalyl chloride had been removed. The resultant acid chloride was redissolved in dry dichloromethane and then treated with N,O-dimethylhydroxylamine hydrochloride (3.61 g). The mixture was cooled in an ice-bath and treated with pyridine (6.0 ml). The mixture was then allowed to stir at room temperature for 1.5 h and then diluted with ether (100 ml) and washed with brine. The organic layer was then dried (MgSO4) and evaporated to leave an oil. This was the chromatographed on silica gel, loading in dichloromethane, and eluting, with ethyl acetate/hexane mixtures to give, after evaporation of requisite fractions, the hydroxamate (5.2 g) as a solid; υmax(CH2Cl2) 2982, 2937, 1641, 1489, 1445, 1379,and 975 cm−1; δ(CDCl3) 1.43 (3H, t, J 7.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s, ), 4.13 (2H, q, J 7.3 Hz), 6.49 (1H, s); (Found m/z 197.1164. C9H15N3O2 requires m/z 197.1164).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[CH2:6][CH2:5]2.[Br:17][CH2:18][CH2:19][CH2:20]Br>[H-].[Na+].C(OCC)(=O)C>[Br:17][CH:18]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:7]21[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]2)[CH2:19][CH3:20]
Reactant: BrCCCBr
Reactant: O=C1NC(=O)C2(CCc3cc(F)ccc32)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(Br)C1Cc2cc(F)ccc2C12NC(=O)NC2=O
Temperature: 50 °C

Procedure:
(+/−)-5′-fluoro-spiro[imidazolidine-4,1′indan]-2,5-dione (331 mg.,1.5 mmol) was dissolved in dry dimethylformaride (4 mL) and 60% sodium hydride in mineral oil (72 mg., 1.8 mmol) was added. The mixture was warmed at 50° C for 20 minutes and then 1,3-dibromo-propane (1.1 mL, 10.9 mmol) was added. The reaction mixture was warmed at 50° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate and the organic solution was washed with aqueous Na2CO3 and water (3×). The dried extract was evaporated and chromatographed on silica gel using a 10-30% ethyl acetate/hexane gradient. The appropriate fractions were combined and evaporated to give the racemic product as a glassy solid which was used as is.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:6]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: Cc1ccc(-n2cnnn2)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4C)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methyl-5-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[F:23]C1C=CC(C(Cl)=O)=CC=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:23])=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3ccc(F)cc3)n(CCN)cc2n(C)c1=O

Procedure:
This compound was prepared analogously to Intermediate A by replacing benzoyl chloride (step 2) with 4-fluorobenzoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-hydoxybenzoate (6.85 g, 45 mmole) in 80 ml DMF was added potassium tert. butoxide (5.6 g, 51 mmole) and the mixture was stirred at room temperature for one hour. 4-Methoxybenzyl chloride (8.3 g, 52 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and 200 ml ethyl acetate was added. The organic phase was washed four times with water, dried with sodium sulfate and evaporated under reduced pressure. Yield: 12.3 g=100%
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=1[OH:25].C[O:27][C:28](=[O:37])[CH:29](Br)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:30][CH:29]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:25][C:18]3[C:19]([F:24])=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=3[F:16])[CH:6]=[N:5]2)[C:28]([OH:27])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Cc1ccc(F)c(O)c1F
Product: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1F

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-3-methyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded impure 3-cyclopentyl-2-[4-(2,6-difluoro-3-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as an oily light brown semi-solid (716.0 mg, 87% for the final step) and was used in Example 107.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:17][C:18]1[S:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][C:19]=1[CH3:26].CC(OC)(C)C>C1COCC1>[Br:17][C:18]1[S:22][C:21]([C:23](=[O:25])[CH2:24][C:11]([C:6]2[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=2)([OH:16])[C:12]([F:13])([F:14])[F:15])=[CH:20][C:19]=1[CH3:26]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc(C)c(Br)s1
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)sc1Br
Reaction time: 2 h
Yield: 111.4 %

Procedure:
LiH (2.06 g) is added to a solution of 3′,5′-dichloro-2,2,2-trifluoroacetophenone (48.0 g) and 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (30.3 g) in THF (1000 ml). After 2 hours at 60° C. MTBE is added (300 ml) and the reaction mixture is poured onto water (500 ml) at 0° C. The organic phase is extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 71.2 g of 1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one. The crude product is used without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:8]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:25][C:2]([F:24])([F:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:34])[CH:8]=1
Reactant: FC(F)(F)CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(Cc1cc(OCCCC(F)(F)F)ccn1)c1nc2ccccc2[nH]1

Procedure:
The thus-obtained 2-[4-(4,4,4-trifluorobutoxy)pyridin-2-yl-methylthio]-1H-benzimidazole (1.27 g) was dissolved in methylene chloride (20 mL). A solution of 80% m-chloroperbenzoic acid (746 mg) in methylene chloride (10 mL) was added dropwise at −30° C., and the mixture was stirred for an hour at the same temperature. A saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture. The temperature of the mixture was returned to room temperature, and the mixture was stirred for 10 minutes, followed by extraction with methylene chloride. The organic layer was washed sequentially with water and brine, and brought to dryness over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel: NH-DM1020 (product of Fuji Silicia), chloroform:methanol=10:1), whereby 2-[4-(4,4,4-trifluorobutoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole was obtained (1.2 g).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([O:10][CH:11]2[CH2:14][N:13]([C:15]([CH3:35])([CH3:34])[CH2:16][CH2:17][C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([NH2:21])=[O:20])[CH2:12]2)=[CH:8][C:7]=1[O:38]C>ClCCl>[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([O:10][CH:11]2[CH2:12][N:13]([C:15]([CH3:34])([CH3:35])[CH2:16][CH2:17][C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([NH2:21])=[O:20])[CH2:14]2)=[CH:8][C:7]=1[OH:38]
Reactant: COc1cc(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2ccc(Cl)c(O)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Boron tribromide (1M in dichloromethane, 1.75 mL, 1.75 mmol) was added to an ice-cooled solution of the product of example 113 (180 mg, 0.36 mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for 1.5 hour. The reaction was then quenched with 0.88 ammonia (30 mL) and the solution stirred at room temperature for 18 hours. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane to dichloromethane/methanol/0.88 ammonia (97:3:0.3), afforded the title compound as a colourless foam in 93% yield, 270 mg
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[F:11].[CH2:12](I)C>C(O)C.O>[F:11][C:3]1[CH:4]=[C:5]([S:8][CH2:9][CH3:12])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CCI
Reactant: N#CSc1ccc(N)c(F)c1
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7 mL) was added dropwise to a solution of Na2S.9H2O (714 mg, 2.97 mmol) in water (1.5 mL) and the resulting mixture stirred at 50° C. for 1 hour. A solution of ethyl iodide (510 mg, 3.27 mmol) in ethanol (1 mL) was then added and the reaction stirred at 50° C. for a further 6 hours. The mixture was diluted with water (30 mL) and extracted with Et2O (4×10 mL), then the combined Et2O extracts washed with water (3×20 mL), saturated NaCl (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a pale yellow oil which was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to afford 2-fluoro-4-ethylthioaniline as a colourless oil (470 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J=11.3, 2.0 Hz, 1 H), 7.01 (ddd, J=8.2, 2.0, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.81 (br s, 2 H), 2.80 (q, J=7.3 Hz, 2 H), 1.24 (t, J=7.3 Hz, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[C:20]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][CH2:32][C@H:28]3[CH2:27][NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC[C@H]3CNc3ccccc3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 77 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (S)-phenyl-pyrrolidin-2-ylmethyl-amine as described in Steps 5 and 6, Example 24 to give the title compound as a yellow glass (77% yield). LC/MS: RT 3.29 min, m/e 458 (M+H); 1H NMR (δ, ppm): 11.84 (1H, s), 7.65 (1H, d), 7.35 (1H, s), 7.25 (1H, d), 7.14 (2H, t), 6.74 (2H, d), 6.62 (1H, t), 3.76 (1H, m), 3.34-3.45 (2H, m), 3.06-3.20 (2H, m), 2.39 (2H, q), 2.30 (3H, s), 1.86 (2H, m), 1.51-1.58 (2H, m), 1.09 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=S.[NH:11]([C:13](=[O:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)=[O:15])[NH2:12].N=C=N>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:29][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[N:11][N:12]=1
Reactant: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Reactant: Fc1ccccc1N=C=S
Agent: N=C=N
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1nnc(Nc2ccccc2F)o1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
2-Fluorophenylisothiocyanate (92 μL, 0.75 mmol) was added to a stirred suspension of 2-hydrazino-N-(4-morpholin-4-ylphenyl)-2-oxoacetamide (Intermediate 16, 160 mg, 0.6 mmol) in DMF (10 mL) and stirred at 50° C. until a clear solution was obtained. PS-Carbodiimide (909 mg, 1.2 mmol) was added and the reaction was heated at 80° C. for a further 4 h. The reaction was filtered and the resin washed with DMF (5 mL). The combined DMF solutions were concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a yellow powder (190 mg, 82%):
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.CN1CCOCC1>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(CCO)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
4-Nitrophenyl chloroformate (9.85 g, 49 mmol) was dissolved in DCM (200 mL), and cooled to 0° C. 2-(4-methylpiperazin-1-yl)ethanol (7.2 g, 50 mmol) and NMM (6 mL) were added, and the reaction mixture was allowed to warm gradually to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution until the yellow colour extracted into the aqueous layer had disappeared. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (10.7 g, 71%) as a yellow oil which solidified on standing.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:28])[NH:26][NH2:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:27][NH:26][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[OH:17])=[O:28])[C:7]2=[O:15]
Reactant: NNC(=O)Nc1ccccc1O
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(=O)Nc3ccccc3O)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, 4-(2-hydroxyphenyl)-semicarbazide hydrochloride; reflux for 5 hours