Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:47])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:48]([NH:51][C:52]1[S:53][C:54]([S:58](Cl)(=[O:60])=[O:59])=[C:55]([CH3:57])[N:56]=1)(=[O:50])[CH3:49]>>[CH3:2][O:3][C:4](=[O:47])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH3:46])=[CH:42][CH:43]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:58]([C:54]1[S:53][C:52]([NH:51][C:48](=[O:50])[CH3:49])=[N:56][C:55]=1[CH3:57])(=[O:59])=[O:60])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CCOc1ccc([C@H]2COc3cc4c(cc3O2)CNC(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)C4)cc1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Product: CCOc1ccc([C@H]2COc3cc4c(cc3O2)CN(S(=O)(=O)c2sc(NC(C)=O)nc2C)C(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)C4)cc1
Yield: 73.9 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-(4-ethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester hydrochloride (18 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (11 mg) according to General Procedure E to give (S)-2-{[(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-(4-ethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (17 mg). This was hydrolyzed according to General Procedures N and B to give the title compound (5 mg). LCMS: (m/z) 783.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]3[CH:10]=[CH:9][C:8]([CH:7]4[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]4[OH:1])=[CH:13][CH:12]=3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: BrCCCOc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc4c(c3)OCO4)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.859 g of 5-(3-bromopropoxy)benzo[1,3]dioxole are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.10 (1:2 EtOAc-heptane); Rt=4.96.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[N:7][CH:6]=1)[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21]O)[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([O:11][CH2:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: OCCc1cccc(Cl)c1
Reactant: CCOC(=O)c1cncc(O)c1
Product: CCOC(=O)c1cncc(OCCc2cccc(Cl)c2)c1

Procedure:
5-Hydroxy-nicotinic acid ethyl ester and 2-(3-chlorophenyl)ethanol were etherified in a Mitsunobu reaction in analogy to step 3 of example 3 to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.5 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 4-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (54 mg, 45%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[CH:17]=1.C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[C:37]([C@@H:38]2[CH2:40][O:39]2)=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][O:32][C:33]2=[O:41]>C(O)C>[OH:39][C@H:38]([C:37]1[C:29]([CH3:28])=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:41])[O:32][CH2:31]2)[CH2:40][N:9]1[CH2:8][CH2:7][C:5]2([C:4](=[O:12])[N:3]([C:13]3[CH2:14][O:15][C:16](=[O:18])[CH:17]=3)[CH:2]([CH3:1])[CH2:6]2)[CH2:11][CH2:10]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)CC(C)N(C2=CC(=O)OC2)C3=O)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
3-Methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22, 0.257 mmol) was dissolved in ethanol (3 mL), and treated with diisopropylethylamine (135 μl, 0.771 mmol) followed by (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (I-4B, 73.3 mg, 0.385 mmol). The mixture was heated at 80° C. in a sealed tube for 12 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude product was purified by column chromatography eluting with a 0-20% MeOH/EtOAc gradient to give the title product as a mixture of diastereomers. LC-MS (IE, m/z): 441.3 (M+1)+.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[N:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([N:19]=[C:20]=[N:21]C1C=NC=CC=1)(C)(C)C>>[C:20]([N:21]=[C:7]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])#[N:19]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CCCCCN=C=Nc1cccnc1
Product: CCCCCNC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-n-pentyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 130.4°-131.6° C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[C:12]1(/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccccc1
Agent: Cl
Product: O=C(/C=C/c1ccccc1)N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-phenylpropenoic acid; MS (ES+) 257 (MH+).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][O:6][C:7]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([CH2:57][CH:58]([CH:68]=O)[CH2:59][CH2:60][CH2:61][CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH:42]=[C:43]([F:56])[C:44]=1[O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48]>>[F:38][C:39]1[CH:40]=[C:41]([CH:42]=[C:43]([F:56])[C:44]=1[O:45][Si:46]([CH:47]([CH3:49])[CH3:48])([CH:50]([CH3:52])[CH3:51])[CH:53]([CH3:54])[CH3:55])[CH2:57][CH:58]([CH:68]=[CH:9][C:8]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:7]=1[O:6][CH2:5][C:4]1[CH:34]=[CH:35][CH:36]=[CH:37][C:3]=1[Cl:2])[CH2:59][CH2:60][CH2:61][CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64]
Reactant: CCOC(=O)CCCCC(C=O)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Reactant: Fc1ccc(OCc2ccccc2Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: CCOC(=O)CCCCC(C=Cc1cc(F)ccc1OCc1ccccc1Cl)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1

Procedure:
Reaction in analogy to Example 21A of [2-(2-chlorobenzyloxy)-5-fluorobenzyl]tri-phenylphosphonium bromide and ethyl 7-(3,5-difluoro-4-triisopropylsilanyloxyphenyl)-6-formylheptanoate results in the title compound with 70% of theory as E/Z mixture (2:1).
Reaction SMILES: CSC(=NC)[N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9]C=1)[CH3:5].C[NH:17]C(N(C)CC1C=CN=CC=1)=S>[N+](C)([O-])=O>[CH3:5][NH:4][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:17]=1
Reactant: CNC(=S)N(C)Cc1ccncc1
Reactant: CN=C(SC)N(C)Cc1ccc(Cl)cc1
Solvent: C[N+](=O)[O-]
Product: CNCc1ccccn1

Procedure:
To 4.98 g (0.0205 mole) of S-methyl-N-(4-chlorobenzyl)-N-methyl-N'-methylisothiourea prepared in (1) was added 25 ml of nitromethane and the mixture was refluxed for 6.5 hours. The nitromethane was distilled off and the residue was subjected to silica gel (240 g) column chromatography using MeOH-CHCl3 (1:10) as an eluent to give 5.23 g of an orange-colored oil. To this oil were added small amounts of EtOH and ether and the mixture was cooled in a dry ice-acetone bath and triturated to give crystals. After addition of ether, the crystals were collected by filtration, washed with ether and dried. The procedure gave 3.69 g of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A mixture of methyl 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoate (865 mg, 1.34 mmol) in MeOH (10 mL)/THF (20 mL) and LiOH (2 N, 10 mL) was stirred at rt overnight. The reaction mixture was made acidic by addition of 1 N HCl to pH=1-2 and concentrated. The resulting residue was partitioned between EtOAc and sat. NaCl. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO (40 g siligel column, 0-10% MeOH/DCM over 30 min) to yield 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoic acid as a colorless oil (650 mg, 81% yield). LCMS: RT=2.17 min [M+H] 600.88 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0. % TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.45 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([O:20][CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][N:46]4[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]4)(=[O:29])=[O:28])[CH2:25][CH2:26]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(S(=O)(=O)CCN3CCN(S(C)(=O)=O)CC3)CC2)nc(N2CCOCC2)n1
Yield: 28 %

Procedure:
Reaction of 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole with 1-(methylsulfonyl)piperazine as in Example 12 gave 2-(difluoromethyl)-4-methoxy-1-[4-{[1-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 28% yield: mp (MeOH) 251-254° C.; 1H NMR (DMSO-d6) δ 7.96 (d, J=8.3 Hz, 1H), 7.71 (t, JHF=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 5.28-5.22 (m, 1H), 3.98 (s, 3H), 3.85-3.84 (m, 4H), 3.74-3.70 (m, 4H), 3.52-3.46 (m, 2H), 3.34-3.20 (m, 4H), 3.13-3.11 (m, 4H), 2.86 (s, 3H), 2.78-2.74 (m, 2H), 2.56-2.54 (m, 4H), 2.13-2.08 (m, 2H), 1.88-1.80 (m, 2H); Anal. Calcd. for C28H39F2N9O7S2: C, 47.0; H, 5.5; N, 17.6. Found: C, 47.2; H, 5.4; N, 17.4%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:15][O:16][CH3:17])[CH:8]=[O:9]
Reactant: CN(C)c1cc(C=O)ccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C=O)cc1N(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 1.90 g, 47.5 mmol) in dry DMF (60 ml) was added dropwise a solution of the compound (3) (5.98 g, 36.2 mmol) obtained above in DMF (40 ml) under nitrogen atmosphere under ice-cooling. The mixture was stirred at 0° C. for 30 minutes, and thereto was added dropwise chloromethyl methyl ether (3.6 ml, 47.4 mmol). The reaction mixture was stirred at 0° C.-room temperature for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The concentrate was purified by column chromatography on silica gel to give the title aldehyde compound (Compound A) as yellow liquid. Yield 7.17 g (95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[NH2:14])[CH:5]=[CH:6][C:7]=1[F:8].C1CCN2C(=NCCC2)CC1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCCC1c1ccc(F)c(F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3,4-difluoro-phenyl)-cyclopentylamine (1.40 g, 7.10 mmol) from preparation 15, methylene chloride (20.0 mL) and the solution cooled to 0° C. DBU (1.27 mL, 8.52 mmol) and isopropylsulfonyl chloride (0.96 mL, 8.52 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 910 mg (42%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16]Cl)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][S:25][C:24]=2[CH:34]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16][N:31]3[CH2:32][CH2:33][CH:28]([C:27]4[C:23]5[CH:22]=[CH:21][C:20]([F:19])=[CH:34][C:24]=5[S:25][CH:26]=4)[CH2:29][CH2:30]3)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: CCc1sc2c(c1CCCl)CCN(C(C)=O)C2
Agent: Cl
Product: CCc1sc2c(c1CCN1CCC(c3csc4cc(F)ccc34)CC1)CCN(C(C)=O)C2

Procedure:
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([S:15][CH2:16][C:17]([OH:19])=O)[N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:33][C:34]([CH:36]1[CH2:38][CH2:37]1)=[NH:35]>CN(C=O)C>[CH2:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:15][CH2:16][C:17]2[O:19][N:35]=[C:34]([CH:36]3[CH2:38][CH2:37]3)[N:33]=2)=[N:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=C(NO)C1CC1
Reactant: Nc1nc(SCC(=O)O)ncc1Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nc(SCc2nc(C3CC3)no2)ncc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
A solution of (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid (0.35 mg, 1.27 mmol) as prepared according to the method described in example 22, and 1,1′-carbonyl-diimidazole (0.31 g, 1.91 mmol) in DMF (8 ml) was stirred at room temperature for 3 h and subsequently N-hydroxy-cyclopropanecarboxamidine (0.19 g, 1.91 mmol) was added. The reaction mixture was stirred at 80° C. for 20 h and evaporated. Acetic acid (10 ml) was added and the stirred mixture was heated under reflux conditions for 2 h. Aqueous work-up, column chromatography on silica gel (ethyl acetate/hexane 3:2) and crystallization from ethyl acetate/hexane yielded the title compound (36 mg, 9%) as an off-white solid, m.p. 94° C. and MS: m/e=340.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].O.NN.C([O-])(=O)C.[Na+].Br[CH:22]([CH3:24])[CH3:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:22]([CH3:24])[CH3:23])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CC(C)Br
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of 4-bromo-3-fluorobenzene-1-sulfonyl chloride (5.40 mL, 36.5 mmol) in THF (150 mL) at 0° C. was added hydrazine monohydrate (6.20 mL, 63.9 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours. The solvent was removed in vacuo and replaced with heptanes (150 mL) and the resulting precipitate was collected by filtration. The solid was dissolved in industrial methylated spirit (150 mL) and to this solution was added sodium acetate (17.9 g, 218 mmol) and 2-bromopropane (17.2 mL, 183 mmol). The resultant reaction mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with water (300 mL) before being extracted with CH2Cl2 (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:heptanes 20/80 to afford title compound as a colourless solid in 12% yield, 1.19 g.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([OH:16])[CH3:15].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([O:16][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)COc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(C)COc2c([N+](=O)[O-])ccc(F)c2F)cc1
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a solution of 4.5 g of the compound obtained in Example 5 in 8.6 ml of pyridine was added 4.36 g of p-toluenesulfonyl chloride and the mixture was stirred under cooling with ice for 4 hours, and then at room temperature for 4 hours. To the mixture were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 6.52 g of the titled compound.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])(=[O:5])=[O:4])[CH3:2]>[Pd].O.C(O)C>[CH2:1]([S:3]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)=[O:8])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCS(=O)(=O)NC(=O)c1cccc(N)c1
Yield: 73.6 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(ethylsulphonylaminocarbonyl )-3-nitrobenzene (3 g, 11.6 mmol), 10% palladium on carbon (0.3 g, 10% (w/w)) in water (3 ml) and ethanol (100 ml), the title compound (1.95 g, 74%) was afforded as a pale beige solid after recrystallisation from ethanol. mp 129°-132° C. 1H NMR (360 MHz, D6 -DMSO) δ 1.24 (3H, t, J=7.4 Hz), 3.47 (2H, q, J=7.4 Hz), 5.40 (2H, brs), 6.77-6.83 (1H, m), 7.02-7.08 (2H, m), 7.13 (1H, dd, J=7.8 and 7.7 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([NH2:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][C:7]([N:10]3[C:14](=[O:15])[C:13]4[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:16])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc2cc[nH]c2n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccc2cc[nH]c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-6-ylamine (0.12 g, 0.9 mmol) was suspended in acetic acid (1.5 mL), then phthalic anhydride (133 mg, 0.9 mmol) and sodium acetate (118 mg, 1.44 mmol) were added and the mixture heated to 120° C. After 3 h, the mixture was concentrated in vacuo, the residue obtained dissolved in ethyl acetate, and then cooled to 0° C. Ice-water and sodium bicarbonate solution were added then the aqueous layer was extracted with ethyl acetate. The aqueous layer was adjusted to pH 6 with 1M HCl solution and was extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate then concentrated in vacuo. Purification by chromatography (silica, 20 to 70% ethyl acetate in hexanes) gave 2-(1H-pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (179 mg, 75%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.91 (br. s., 1H) 8.15 (d, J=7.9 Hz, 1H) 7.90-8.05 (m, 4H) 7.59-7.65 (m, 1H) 7.21 (d, J=7.9 Hz, 1H) 6.54-6.60 (m, 1H); LCMS (EI/CI) m/z: 264 [M+H].