Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>ClCCl.C(O)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][NH:11][O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Clc1ccc(C=NOCCCN2CCOCC2)cc1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc(CNOCCCN2CCOCC2)cc1Cl
Temperature: 60 °C
Yield: 94 %

Procedure:
A solution of 3,4-dichlorobenzaldehyde O-(3-morpholin-4-yl-propyl)-oxime (0.160 g, 0.5 mmol) in a mixture of dichloromethane (2 ml) and acetic acid (1 ml) was treated with borane-pyridine complex (0.17 ml, 1.36 mmol) and the resulting mixture was heated under reflux (bath temperature 60° C.) for 4 h. The solvent was then evaporated under reduced pressure and the residue was treated with 10% aqueous hydrochloric acid (3 ml). The reaction mixture was then basified with solid sodium carbonate and extracted with ethyl acetate. The organic phase was then washed with brine, dried (anhydrous magnesium sulfate) and concentrated to give 0.150 g (93% yield) of the crude title hydroxylamine as a light yellow oil which was used as such for the acylation step. 1HNMR 400 MHz (C6D6) δ (ppm): 1.66 (2H, m, CH2), 2.22 (2H, t, J=7.1 Hz, NCH2), 2.24 (4H, m, NCH2), 3.56 (2H, s, NCH2), 3.69 (4H, m, OCH2), 3.70 (2H, t, J=6.5 Hz, OCH2), 5.2 (1H, broad, NH), 6.82 (1H, dd, J=1.9 Hz and J=8.5 Hz, aromatic), 7.13 (1H, d, J=8.5 Hz, aromatic), 7.33 (1H, d, J=1.9 Hz, aromatic).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16]C(=O)C(F)(F)F)[CH2:6]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH2:16])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCO[C@@H]1C[C@H](N)c2cc(OC)ccc21
Yield: 87.6 %

Procedure:
Step U (2): N-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (1.28 g, 4.06 mmol) from Step U (1), potassium carbonate (2.85 g, 20.8 mmol) and MeOH (92 mL)/H2O (6 mL) were heated at reflux for 16 h. The reaction mixture was concentrated in vacuo. Added water to the residue, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4, filtered and concentrated to afford 780 mg (quantitative yield) of the title compound as light brown oil. HRMS (M+H)+=220.1336; [α]D +18.72 (c=8.86 mg/mL, ethanol) 1H NMR (500 MHz, CDCl3) δ ppm 1.66 (s, 1H) 1.76 (d, J=12.82 Hz, 1H) 2.74-2.83 (m, 1H) 3.81 (s, 3H) 4.04-4.18 (m, 3H) 4.77 (t, J=5.80 Hz, 1H) 5.18 (dd, J=10.38, 1.53 Hz, 1H) 5.32 (dd, J=17.24, 1.68 Hz, 1H) 5.97 (dd, 1H) 6.90 (d, J=2.44 Hz, 1H) 7.30 (d, J=8.24 Hz, 1H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]1.C([BH3-])#N.[Na+]>[Cl-].[Zn+2].[Cl-]>[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][CH2:21][CH:20]([N:14]2[CH2:15][CH2:16][N:11]([CH:8]3[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]3)[CH2:12][CH2:13]2)[CH2:19]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: CC(C)(C)C1CCC(N2CCNCC2)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Product: CC1(C)CCCC(N2CCN(C3CCC(C(C)(C)C)CC3)CC2)C1

Procedure:
5.0 g (22.3 millimoles) of N-(4-tert-butylcyclohexyl)-piperazine, 5.4 g (44.6 millimoles) of 3,3-dimethylcyclohexanone, 1.7 g (12.3 millimoles) of zinc(II) chloride and 1.6 g (24.5 millimoles) of sodium cyanoborohydride are stirred for 48 hours at 20° C. The mixture is evaporated down under reduced pressure, the residue is hydrolyzed with 1N sodium hydroxide solution and the mixture is extracted with methyl tert-butyl ether. Working up the organic extract in the usual manner gives 3.7 g (50% of theory) of a product in the form of white crystals (mp. 90°-92° C.; for IR data, see Table 1b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](=[CH:13][N:14]([CH3:16])C)[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25](N)C>C(Cl)(Cl)Cl>[CH2:16]([NH:14][CH:13]=[C:9]1[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:6]2[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12])[CH3:25]
Reactant: CCN
Reactant: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Solvent: ClC(Cl)Cl
Product: CCNC=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Temperature: 100 °C

Procedure:
A mixture consisting of 5 gm of 7-chloro-5-(2'-chloro-phenyl)-1,3-dihydro-3-(dimethylamino-methylene)-2H-1,4-benzodiazepin-2-one and 75 ml of ethylamine was heated for 20 minutes at 100°C in closed tube. Thereafter, the reaction mixture was quickly cooled, diluted with chloroform and evaporated to dryness in vacuo. The yellow, solid residue was recrystallized from absolute ethanol, yielding the compound of the formula ##SPC7##
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C.ClCCl.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:47]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N:40]=[C:39]([NH2:48])[C:38]=2[N:37]=[C:36]1[CH2:49][CH2:50][CH2:51][CH3:52]>CO>[NH2:48][C:39]1[C:38]2[N:37]=[C:36]([CH2:49][CH2:50][CH2:51][CH3:52])[N:35]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][S:13]([C:8]3[C:9]4[C:4](=[C:3]([N:2]([CH3:17])[CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH:5]=[CH:6][CH:7]=3)(=[O:15])=[O:14])[C:47]=2[C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N:40]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
5-Dimethylamino-1-naphthalenesulfonyl chloride (1.82 g, 6.74 mmol) was added to a mixture of N,N-diisopropylethylamine (1.23 mL, 7.06 mmol), dichloromethane (15 mL) and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.42 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. Methanol was added to the reaction mixture until a clear solution was obtained. Silica gel was added to the reaction mixture and then the solvents were removed. The silica gel was placed in a column and then eluted with chloroform in a stepwise gradient to 9:1 chloroform:methanol. The resulting product was recrystallized from N,N-dimethylformamide and deionized water to provide 2.5 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamide as a yellow crystalline solid, m.p. 223-224° C. Analysis: Calculated for C30H36N6O2S: %C, 66.15; %H, 6.66; %N, 15.43; Found: %C, 66.36; %H, 6.34; %N, 15.23.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH3:11])[CH:7]=[CH:6]2.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[H-].[Na+].[CH2:45]([C:47]1[NH:48][C:49]2[C:50]([N:57]=1)=[N:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])[CH3:46]>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH2:11][N:57]1[C:50]3=[N:51][C:52]([CH3:56])=[CH:53][C:54]([CH3:55])=[C:49]3[N:48]=[C:47]1[CH2:45][CH3:46])[CH:7]=[CH:6]2
Reactant: CCOC(=O)c1ccccc1-n1nc2ccc(C)cc2c1Br
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-n1nc2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2c1Br
Yield: 33.1 %

Procedure:
Carbon tetrachloride (2 ml) was added to ethyl 2-(3-bromo-5-methyl-2H-indazol-2-yl)benzoate (0.450 g, 1.25 mmol) as obtained in Reference Example 4, and the mixture was stirred. Thereto were added N-bromosuccinimide (0.223 g, 1.25 mmol) and azobisisobutyronitrile (21 mg, 0.125 mmol), and the mixture was refluxed under heating for 3.5 hours. After cooling, it was filtered, and the cake was washed with dichloromethane (2 ml) and the filtrate was concentrated. The residue was then dissolved in DMF (2 ml), and added to a solution obtained by adding sodium hydride (40 mg, 1.00 mmol) to 2-ethyl-5,7-dimethyl-1H-imidazo[4,5-b]pyridine (0.176 mg, 1.00 mmol) in DMF (4 ml) and stirring the solution for 30 minutes. The mixture was stirred at room temperature for 30 minutes, concentrated, and partitioned by ethyl acetate (10 ml) and water (10 ml). The organic layer was dried over magnesium sulfate, and then filtered. The filtrate was concentrated and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (2:3), whereby 0.176 g of 3-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[CH:20](=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)O.Cl>C(Cl)(=O)C(Cl)=O.C1C=CC=CC=1.N1C=CC=CC=1.O>[CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:27]2[CH:26]=[CH:25][CH:24]=[CH:22][C:21]=2[CH:20]=[O:28])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: O=Cc1ccccc1O
Reactant: CC1=C(C)C(=O)C(CCCCCC(=O)O)=C(C)C1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1=C(C)C(=O)C(CCCCCC(=O)Oc2ccccc2C=O)=C(C)C1=O
Reaction time: 2.5 h

Procedure:
The acid chloride (1.01 part) synthesized from 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the free form) (1 part) and oxalyl chloride (5 volume parts) was dissolved in anhydrous benzene (10 volume parts) and the solution was added dropwise to a solution of salicylaldehyde (0.6 part) in pyridine (10 volume parts) at 25° C. After stirring for 2.5 hours, the reaction mixture was diluted with cold water (300 volume parts) and rendered acidic with dilute hydrochloric acid. It was then extracted twice with diethyl ether (300 volume parts). The extracts were pooled, washed with water and dried. The solvent was then distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel. Elution with chloroform provided a yellow oil of 2,3,5-trimethyl-6-[5'-(o-formylphenyloxycarbonyl) pentyl]-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of o-formylphenolate) (1.3 part). To a cooled, stirred solution of this product (1.1 part) in acetone (25 volume parts) was added standard Jones reagent (2 volume parts). The solution was stirred for 100 minutes, after which it was diluted with cold water (500 volume parts), followed by extraction with ethyl acetate (500 volume parts). The extract was washed with water and dried. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (50 parts). The procedure provided a yellow oil of 2,3,5-trimethyl-6-[5'-(o-carboxyphenyloxycarbonyl) pentyl]-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of o-carboxyphenolate) (1.1 part).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 7.5 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (170 mg, 0.76 mmol) and ethyl isocyanatoacetate (103 μL, 0.92 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), followed by Gilson HPLC separation, gave the desired product (20 mg, 7%). LC-MS (m/z) 352.0 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:27][CH2:26][C:25]1=[O:28]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:24]3[CH2:27][CH2:26][C:25]3=[O:28])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=C1CCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3)CC2)c(C)c1
Yield: 27.5 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and azetidin-2-one (142 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (200 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[O:5].Cl[CH:7]([Cl:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCOCC.O>O1CCCC1>[Cl:15][C:7]1([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:4]([CH2:3][O:2][CH3:1])[O:5]1
Reactant: COCC=O
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COCC1OC1(Cl)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2.106 g of methoxyacetaldehyde, 3.8 ml of terbutyl dichloroacetate and 25 ml of tetrahydrofuran was cooled to -20° C. and over 15 minutes, 29 ml of potassium tertbutylate in tetrahydrofuran (0.9M) were introduced. The mixture stood for 20 minutes and 25 ml of ether and 25 ml of water were added. The mixture was extracted with ether and the organic phase was washed with water saturated with sodium chloride, then dried and concentrated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with methylene chloride to obtain 1.44 g of 1,1-dimethylethyl 2-chloro-3-methoxymethyloxirane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([NH:19][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (150 mg), pyridine (84 μL) and dichloromethane (3 mL) was added benzoyl chloride (72 μL) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained residue was solidified from a mixed solvent of hexane and ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}benzamide (166 mg) as a white powder.
Reaction SMILES: C(OC(=O)N[C@H]1CCN(S(N)(=O)=O)C1)(C)(C)C.[CH2:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:29][CH2:28][N:27]([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:26]1)[CH2:19][CH2:20][CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:76]1[CH:81]=[C:80]([O:82][CH3:83])[N:79]=[C:78]([S:84][CH2:85][C:86]2[CH:91]=[CH:90][CH:89]=[C:88]([F:92])[C:87]=2[F:93])[N:77]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:93][C:87]1[C:88]([F:92])=[CH:89][CH:90]=[CH:91][C:86]=1[CH2:85][S:84][C:78]1[N:77]=[C:76]([NH:33][S:30]([N:27]2[CH2:28][CH2:29][C@H:25]([NH:24][C:23](=[O:34])[O:22][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26]2)(=[O:31])=[O:32])[CH:81]=[C:80]([O:82][CH3:83])[N:79]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CCCCOC(=O)N[C@H]1CCN(S(N)(=O)=O)C1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N[C@H]1CCN(S(N)(=O)=O)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CCCCOC(=O)N[C@H]1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl[(3S)-1-(aminosulfonyl)pyrrolidin-3-yl]carbamate (the product from step i), 0.525 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.429 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine ((the product from example 35 step i), 0.400 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 40 mins. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.75 g
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CSc1ccc(C(=N)Nc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (0.50 g, 33.6 mmol) and 4-fluoroaniline (0.372 g, 33.6 mmol) by following the procedure described in preparation 1, (0.43 g, 49.3%, mp 145-147° C., purity 94.7% by HPLC). 1H-NMR (CDCl3):δ 2.52 (s, 3H), 6.93-6.94 (m, 3H), 7.17-7.32 (m, 5H). MS m/z:261.1(M+)
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)([O-:24])=[O:23].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Yield: 89 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and I, alkylating with 4-nitrobenzyl chloride, in 89% yield, mp 124°-127° C.; MS (Cl) MH+ 329; IR (KBr) 3498, 3076, 2930, 2863, 1656, 1605, 1500, 1466, 1302, 1279, 1184, 1126, 982, 613 cm-1 ; 1H NMR (CDCl3) δ 8.20 (dd, 2H, J=2.0, 6.9 Hz), 7.40 (d, 2H, J=8.8 Hz), 7.03 (m, 2H), 6.93 (m, 1H), 6.75 (d, 1H, J=7.6 Hz), 5.25 (s, 2H), 4.88 (dd, 1H, J=5.4, 7.6 Hz), 3.93 (m, 2H), 2.38-2.17 (m, 2H), 2.10 (m, 1H). Anal. Calc'd for C17H16 N2O5 : C 62.19, H 4.91, N 8.54. Found: C 62.05, H 4.87, N 8.39.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][NH:5][CH2:4]1)[CH3:2].[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:19])[CH3:18]>>[CH2:15]([C:3]1([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][N:5]([C:23]([C:22]2[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:21]=2[O:20][CH:17]([CH3:19])[CH3:18])=[O:24])[CH2:4]1)[CH3:16]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCC1(CC)CNCc2ccc(OC)cc21
Product: CCC1(CC)CN(C(=O)c2cc(S(C)(=O)=O)ccc2OC(C)C)Cc2ccc(OC)cc21

Procedure:
Prepared in analogy to example 1.1 from 4,4-diethyl-6-methoxy-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:18]O)[CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:35])[CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][C:26]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:27]3[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:25]([CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:35])[C:26]3=[O:34])[CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ccc2c(CO)cc(Cl)cc21
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2ccn3C(=O)OC(C)(C)C)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
6-Chloro-4-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester 350 mg, 1.24 mmol and 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (300 mg 1.36 mmol, from Example 2) are dissolved in tetrahydrofuran 6.0 mL and triphenylphospine (630 mg 1.37 mmol) is added in one portion to the reaction. The reaction is cooled to 0° C. and then diisopropyl azodicarboxylate (265 μL 1.37 mmol) is added drop wise to the reaction over 5 minutes, and warmed to room temperature. The reaction is stirred for 15 minutes and then evaporated in vacuo, and purified on silica gel with hexanes ethyl acetate as the eluent to give the title compound (280 mg, 0.58 mmol, 47%). LCMS (ESMS): m/z 484.9 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[O:18][C:19]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:20]=4[CH:21]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8]C(C)C.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[O:18][C:19]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:20]=4[CH:21]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2cc(-c3nc(-c4ccc(OC(C)C)c(I)c4)no3)oc2c1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: COc1ccc2cc(-c3nc(-c4ccc(O)c(I)c4)no3)oc2c1
Yield: 65 %

Procedure:
When the product of Step D was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 65% yield, as colourless solid. 1H-NMR (CDCl3) 8.53 (d, 1H, J=2.01 Hz); 8.06 (dd, 1H, J=8.49, 2.01 Hz); 7.64 (b, 1H); 7.6 (d, 1H, J=8.7 Hz); 7.13 (b, 1H); 7.08 (d, 1H, J=8.46 Hz); 6.98 (dd, 1H, J=8.7, 2.22 Hz); 3.89 (s, 3H).