Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH:10]=O)=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][CH:8]=2)[CH:7]=1
Reactant: O=CNCc1ccc(Cl)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Clc1ccc2cncn2c1
Temperature: 100 °C
Yield: 62.9 %

Procedure:
To a mixture of N-((5-chloropyridin-2-yl)methyl)formamide (740 mg, 4.34 mmol) in toluene (18.4 mL) was added phosphorus oxychloride (1.21 g, 736 μL, 7.89 mmol) and the mixture heated at to 100° C. After 16 h ice was added to the reaction mixture followed by the slow addition of 25% aqueous ammonium hydroxide until pH˜9 was reached. The mixture was diluted with dichloromethane and extracted into dichloromethane (2×). The organic layers were washed with water and brine, dried (MgSO4) and filtered. Purification of the filtrate by chromatography (silica, MeOH/DCM gradient) gave 6-chloroimidazo[1,5-a]pyridine (417 mg, 2.73 mmol, 63.0%) as a brown oil. MS (M+H)+=152.8; 1H NMR (CDCl3) δ: 8.10 (s, 1H), 8.01 (m, 1H), 7.47 (s, 1H), 7.43 (d, J=9.5 Hz, 1H), 6.69 (dd, J=9.5 Hz, 1.5 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].[C:14]([NH:16][C:17]([NH2:19])=[NH:18])#[N:15].[ClH:20]>O>[ClH:20].[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1

Procedure:
A suspension of 3,5-diacetylaniline (0.531 g) in water (8 mL) was treated with cyanoguanidine (0.285 g) and conc. HCl (0.25 mL) and heated at reflux. After 6 hr the mixture was cooled and concentrated and 0.248 g of off-white solid was filtered out and dried to give N-(3,5-diacetylphenyl)biguanide hydrochloride (Compound 12), mp 260°-70° C. (dec).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Ca+2:13].[OH-].C(#N)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[Ca+2:13].[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C([O-])CCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-(4-Piperidyl)propionic acid (20.0 g, 0.12 mol) and calcium hydroxide (14.1 g, 0.19 mol) were suspended in 47 g water and 195 g acetonitrile at 15-25° C. and then cooled to 0-10° C. Benzyl chloroformate (23.9 g, 0.14 mol) was added within 30 minutes and the reaction stirred at 0-5° C. for 2 h. The product precipitated during the reaction and was isolated by filtration to afford the title compound in 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Fc1ccc(CNc2nc(-c3ccccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:20]([N:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[CH:24]=[N:23]1)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44]CCCl>>[ClH:44].[CH2:20]([N:22]1[C:26]([CH3:27])=[C:25]([CH2:28][N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:19][CH2:18]2)[CH:24]=[N:23]1)[CH3:21]
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CCn1ncc(C=O)c1C
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCn1ncc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.183 g, 0.708 mmol) in DCE (8.5 mL). Add 1-ethyl-5-methyl-1H-pyrazole-4-carbaldehyde (0.117 g, 0.850 mmol) followed by sodium triacetoxyborohydride (0.225 g, 1.06 mmol) and stir at room temperature for 18 hr. Purify via SCX chromatography, followed by silica gel chromatography, eluting with 50:50 then 0:100 hexanes:ethyl acetate then 10:90 methanol:ethyl acetate, followed by reverse phase chromatography to give the free base of the title compound (149 mg, 55%). Dissolve the free base (0.138 g, 0.363 mmol) in methanol and add a solution of ammonium chloride (0.019 g, 0.363 mmol) in a minimal volume of methanol. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (149 mg, 99%). MS (ES): m/z=381 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][CH2:12][N:13]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[CH:16][N:15]=1)[CH2:35][CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)nc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-amino]-5-pyridinecarboxylate (850 mg), and sodium hydride (110 mg, 50% dispersion in oil) in DMF (20 ml) was stirred for 15 minutes then iodoethane (150 ml) was added and the mixture stirred for 2 hours. The mixture was diluted with diethyl ether (50 ml) washed with water, dried (MgSO4), filtered through silica gel, evaporated and the residue redissolved in dichloromethane and evaporated to give tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridine carboxylate (800 mg).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])C.[C:20](=O)(SC)OC(OC(=O)CCC)C>>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH2:2][CH2:4][CH3:20]
Reactant: CCCC(=O)OC(C)OC(=O)SC
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Product: CCCC(=O)OC(C)OC(=O)OC1CC(=O)NC1=O

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (4) affords [(1-butanoyloxyethoxy)carbonyloxy]succinimide (18).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.C(N(C(C)C)C(C)C)C.[CH3:58][N:59]([CH3:65])[C:60](=[O:64])[C:61](O)=[O:62]>ClCCl.O>[CH3:58][N:59]([CH3:65])[C:60](=[O:64])[C:61]([N:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:48][CH2:47]1)=[O:62]
Reactant: CN(C)C(=O)C(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.076 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (29.4 mg, 0.091 mmol), N-ethyl-N-isopropylpropan-2-amine (11.82 mg, 0.091 mmol) and 2-(dimethylamino)-2-oxoacetic acid (26.8 mg, 0.229 mmol) in dichloromethane (2 mL) was stirred at 20° C. for 2 hours. The reaction mixture was diluted with distilled water (5 mL), extracted with ethyl acetate (3×4 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow oil (40 mg, 70%). LCMS: m/e 755.68 (M+H)+, 2.42 min (method 11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([F:14])[CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:26][S:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[CH:34]2>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[C:33]3[C:37](=[C:29]([CH2:28][S:27][CH3:26])[CH:30]=[CH:31][CH:32]=3)[NH:36][CH:35]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([F:14])[CH:3]=1
Reactant: CCC(O)(CC)c1ccc(Cl)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (2.77 mmol) of the compound from Example 146A, 585 mg (2.64 mmol) of indium(III) chloride and 301 mg (2.64 mmol) of trifluoroacetic acid were added to 446 mg (2.52 mmol) of the compound from Example 8A in 15 ml of dichloromethane. The reaction mixture was stirred at 80° C. for 1 h. After cooling to RT, the reaction solution was mixed with dichloromethane and silica gel, and the solvent was removed in a rotary evaporator. The residue was purified twice by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 208 mg (22% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH3:15].[H][H]>C(O)(C)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH3:15]
Reactant: COc1c(C)cc(CC=C(C)C)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: COc1c(C)cc(CCC(C)C)cc1C
Yield: 68.8 %

Procedure:
A solution of 2,6-dimethyl-4-(3-methyl-2-butenyl)anisole (10 g, 0.05 mol) in isopropanol (20 mL), together with 5% palladium on carbon (0.1 g) was hydrogenated in a Parr apparatus until the theoretical amount of hydrogen had been consumed. The catalyst was removed by filtration and the solvent evaporated to give a clear residue which was fractionated to afford 7.1 g of the desired product, bp 102°-105° C. (2 mm). NMR (CDCl3) δ0.9 (6H, d), 1.1-2.0 (3H, m), 2.2 (6H, s), 2.5 (2H, t), 3.7 (3H, s), 6.85 (2H, s). IR (film) 3000, 1225, 1025, 870 cm-1. MS (m/e) 206 (M+), 149, 150, 135, 191.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].N1C=CC=CC=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[O:34])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(#N)C.O>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([CH2:31][NH:32][C:33]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:34])[CH:29]=[CH:30][C:22]=2[Cl:21])=[CH:13][C:6]=1[C:7]([NH:9][CH:10]1[CH2:11][CH2:12]1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(C(=O)Cl)c1)c1ccc(Cl)s1
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(NCc1ccc(Cl)c(C(=O)Nc2ccc(Cl)c(C(=O)NC3CC3)c2)c1)c1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 2.0 mL of a 0.05 M solution of 5-amino-2-chloro-N-cyclopropyl-benzamide (0.10 mmol) in acetonitrile was added pyridine (20 μL, 0.25 mmol) and then 1.0 mL of a 0.05 M solution of 2-chloro-5-(5-chloro-thien-2-yl)carbonylaminomethyl-benzoyl chloride (0.10 mmol, prepared from 5-(aminomethyl)-2-chloro-benzoic acid in analogy to step 1c and 1d) in acetonitrile. The reaction mixture was stirred overnight at 60° C., diluted with 200 μL of distilled water and filtered over Alox B. The Alox B pad was washed three times with 2.0 mL 9:1 DMF/MeOH-solution and the combined filtrate was concentrated in vacuo. The residue was dissolved in 2.0 mL of DMF and purified via prep. HPLC.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[F:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28]Br)=[CH:22][CH:21]=1>CN(C=O)C>[F:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][CH:21]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(F)cc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
Under a nitrogen atmosphere, 171 mg of sodium hydride (60% oil dispersion) was added to 15 ml of dry DMF. A solution of 1.0 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.08 g of 3-(4-fluorophenoxy)-benzyl bromide in 20 ml of dry DMF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 1.30 g of the desired compound.
Reaction SMILES: [CH3:1][Li].[OH:3][C:4]1C=C2[C:7]([CH:8]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[CH2:9]C(=O)O2)=[CH:6][CH:5]=1.[CH3:25][CH2:26][O:27][CH2:28][CH3:29]>C(O)(=O)C>[CH3:25][C:26]1([CH3:1])[CH2:9][CH:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:7]2[C:28](=[CH:29][C:4]([OH:3])=[CH:5][CH:6]=2)[O:27]1
Reactant: [Li]C
Reactant: CCOCC
Reactant: O=C1CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Solvent: CC(=O)O
Product: CC1(C)CC(c2cccc3ccccc23)c2ccc(O)cc2O1

Procedure:
To a stirred solution of methyl-lithium in ether (120 ml., 1.9 M solution) at room temperature was added over 0.5 hours finely powdered 3,4-dihydro-7-hydroxy-4-(1-napthyl) coumarin (14.5 g, 0.05 moles). After refluxing for 1 hour a purple solid precipitated out of solution and the reaction mixture was allowed to cool, acidified with dilute hydrochloric acid and extracted with ether (3×). The combined ether extracts were dried and removal of solvent gave a dark coloured oil which was refluxed overnight in glacial acetic acid. The glacial acetic acid was removed in vacuo and the residue dissolved in ether, washed with water, saturated sodium bicarbonate solution and dried. Removal of solvent gave an extremely viscous oil, column chromatography of which on silica, eluting with 40°-60° petrol: ether (gradually increasing concentration of ether) gave the required chroman as a low melting pale yellow solid (9.4 g., 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][NH2:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.CS(C)=O>[NH2:20][C:21]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:17][CH2:16][C:14]1[O:15][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=[CH:18][C:12]=2[CH:13]=1)=[O:24]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 49.5 %

Procedure:
To a dimethylsulfoxide (10 mL) solution of C-(6-benzyloxy-benzofuran-2-yl)-methylamine (300 mg, 1.18 mmol) described in Production Example 1-2-4 were added 2,6-diaminonicotinic acid (181 mg) described in Production Example 1-1-4, 1-hydroxybenzotriazole (319 mg, 2.36 mmol), triethylamine (329 μL, 2.36 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (452 mg, 2.36 mmol) at room temperature, which was stirred at room temperature for 26 hours. To the reaction solution was added water at room temperature followed by extracting with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (227 mg, 60%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O.C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5)c4)c3c2)c1
Yield: 9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-benzyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (60 mg, 0.1 mmol) was hydrolyzed by lithium hydroxide (9 mg, 0.2 mmol) in methanol/water/THF (1/1/1 ml) which afforded 4 mg (9% yield) after purification by preparative TLC (silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.46-8.45 (d, 1H), 8.34-8.33 (d, 1H), 8.14 (s, 1H), 7.9 (s, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.5-7.43 (m, 2H), 7.37-7.33 (m, 2H), 7.3-7.27 (m, 3H), 5.4 (s, 2H), 3.0 (s, 3H). MS: m/z=443.6 (M+1), HPLC: 88.2%, Method A.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]([C:35]1[N:36]=[CH:37][N:38](C(OC(C)(C)C)=O)[CH:39]=1)=[CH2:34]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:38]1[CH:39]=[C:35](/[CH:33]=[CH:34]/[C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[C:8]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=4[S:10][C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[N:36]=[CH:37]1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Reactant: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 14.1 %

Procedure:
To a microwave vial containing 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (20 mg, 0.05 mmol) in DMF (2 mL) was added triethyl amine (0.202 mL, 1.45 mmol), tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (28.2 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (3.40 mg, 4.84 μmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave irradiation. The mixture was cooled to room temperature and diluted with DCM and sat. aq. NH4Cl. The organic layer was collected (phase separator), concentrated in vacuo and purified by reverse phase HPLC (basic condition, 0.1% NH4OH in 1-100% CH3CN/H2O) to afford (E)-3-(4-(2-(1H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (3 mg, 7.03 μmol, 15% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.57 (s, 1H), 7.43 (d, J=8.59 Hz, 2H), 7.30 (d, J=8.59 Hz, 2H), 6.96-7.14 (m, 3H), 6.74-6.96 (m, 4H), 6.53-6.74 (m, 3H). LC/MS (m/z, MH+): 427.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][N:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 59.3 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-4-ylcarbamate (100 mg, 0.370 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (90.7 mg, 0.370 mmol), diisopropylethylamine (0.0645 ml, 0.370 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (80.4 mg, 59.1%) as a solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[SH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH3:22][C:16]([S:13][C:9]1[N:10]=[N:11][S:12][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1nnsc1Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1nnsc1Cc1ccccc1

Procedure:
A solution of 1.99 g of 5-(phenylmethyl)-1,2,3-thiadiazole-4-thiol, sodium salt in 30 ml of ethanol was stirred overnight with 1.96 g of ethyl 2-bromoisobutyrate and then concentrated in vacuo. The residue was taken up in ether, filtered, and evaporated in vacuo. The oily residue was purified as described in Example 50, giving a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 1.22 (t, 3H); 1.67 (s, 2 CH3 's); 4.12 (q, 2H); 4.31 (s, CH2); 7.30 (6s, SH).