Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.Cl[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=1.[NH2:47][C:48]1[CH:71]=[CH:70][C:51]2[O:52][CH2:53][CH2:54][C@@H:55]3[CH2:60][S:59][C:58]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[N:57][C@:56]3([CH3:69])[C:50]=2[CH:49]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:46][C:45]1[C:40]([NH:47][C:48]2[CH:71]=[CH:70][C:51]3[O:52][CH2:53][CH2:54][C@@H:55]4[CH2:60][S:59][C:58]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[N:57][C@:56]4([CH3:69])[C:50]=3[CH:49]=2)=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@@H]2CS1
Reactant: Clc1cccnc1Cl
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(Nc4ncccc4Cl)ccc3OCC[C@@H]2CS1
Reaction time: 1 h
Yield: 99 %

Procedure:
An oven dried vial was charged with brettphos precatalyst (12 mg, 0.014 mmol), brettphos (7.6 mg, 0.014 mmol), 2,3-dichloropyridine (8.5 mg, 0.058 mmol), tert-butyl rel-((4aS,11bS)-10-amino-11b-methyl-4a,5,6,11b-tetrahydro-4H-benzo[2,3]oxepino[4,5-d][1,3]thiazin-2-yl)carbamate from preparation I (25 mg, 0.069 mmol) and LiHMDS (14 mg, 0.086 mmol). The vial was purged with nitrogen. Dioxane (1 mL) was added. The vial was placed in a preheated oil bath at 100° C. for 1 h. The reaction was then diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with water, brine, and dried over sodium sulfate. The organic layer was filtered and concentrated in vacuo to afford tert-butyl rel-((4aS,11bS)-10-((3-chloropyridin-2-yl)amino)-11b-methyl-4a,5,6,11b-tetrahydro-4H-benzo[2,3]oxepino[4,5-d][1,3]thiazin-2-yl)carbamate (27 mg, 0.057 mmol, 99% yield). The crude material was used in the next step without further purification. MS (M+H)+=475.26.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:32][C:7]1[CH:2]=[CH:3][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:5][CH:6]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(Cl)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-Chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-chloro-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)N(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C(C)C)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-isopropyl-N-methylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]1([C:18]2([CH2:21][CH2:22]O)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:26]=1[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(O)=O>[C:37]1([C:35]2[C:26]3[C:25](=[C:30]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:28][CH:27]=3)[N:24]=[CH:22][C:21]=2[C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Reactant: OCCC1(c2ccccc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(C3(c4ccccc4)CC3)cnc12
Temperature: 120 °C
Yield: 17 %

Procedure:
Pyridinium chlorochromate (0.417 g, 1.94 mmol) in CH2Cl2 (3 mL) is treated with a mixture of 2-(1-phenylcyclopropyl)ethanol (0.157 g, 0.967 mmol) in CH2Cl2 (2 mL) for 2 h. The reaction is filtered through Celite, treated with AcOH (3 mL) and [2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone (0.128 g, 0.484 mmol), and the methylene chloride is removed in vacuo. Then 1:20H2SO4:AcOH (0.1 mL) is added and the reaction is heated at 120° C. for 3.5 h. The cooled reaction is poured into saturated aq sodium bicarbonate and extracted with ethyl acetate. The extract is washed with saturated aq sodium bicarbonate and dried (MgSO4). The residue is chromatographed eluting with 5:95 ethyl acetate:hexane and then prep HPLC with a gradient of 10-100% acetonitrile/water to afford the title compound (0.032 g). HRMS: calcd for C25H18F3N+H, 390.14696; found (ESI, [M+H]+), 390.1468.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:35]([CH3:37])[CH3:36])[N:9]=[C:10]([C:11]3[N:12](C(OC(C)(C)C)=O)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([O:20]CC3C=CC=CC=3)=[CH:15][CH:14]=4)[C:3]=12.C(O)=O.Cl>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:35]([CH3:37])[CH3:36])[N:9]=[C:10]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=4)[C:3]=12
Reactant: CC(C)n1nc(-c2cc3cc(OCc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: CC(C)n1nc(-c2cc3cc(O)ccc3[nH]2)c2c(N)ncnc21
Reaction time: 1 h

Procedure:
BA24 (3-(4-fluoro-3-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 30 mg, 0.10 mmol) was dissolved in a solution of formic acid (4.5 ml, 10 equivalents) and HCl (0.45 ml, 1 equivalent). The reaction was heated and stirred for one hour under an argon atmosphere. The reaction was then concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA24dd. ESI-MS (M+H)+ m/z calcd 309.1, found 309.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1,3-butanedione (0.6 g) and diethyl oxalate (0.83 ml) in 1,2-dimethoxyethane (2 ml) was added to a stirred suspension of sodium hydride (0.44 g, 50% dispersion in mineral oil, washed with petrol 40-60° C.) in 1,2-dimethoxyethane (5 ml) under nitrogen. The stirred mixture was heated under reflux for 1 hour, cooled and acidified with 2M hydrochloric acid (10 ml). The brown solid which formed was recrystallised from ethanol-water to give the title product (mp 93-94° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)=[CH2:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-quinolin-6-yl-ethanol (Stage 154.1, 50 mg, 0.154 mmol) was dissolved in acetic acid >99% (0.150 mL) and sulfuric acid conc. 98% (0.050 mL) and the mixture was heated to reflux for 1 h. After cooling down to rt, ice water was added. The mixture was basified with NaOH 1 N and extracted with EtOAc twice. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by preparative HPLC with acetonitrile/water (with 0.1% TFA) to afford the title compound as a yellow solid (tR 1.10 min (conditions 1), (MH+=307).
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[C:10]4[C:15]([N:16](S(C5C(C(C)C)=CC(C(C)C)=CC=5C(C)C)(=O)=O)[CH:17]=3)=[CH:14][CH:13]=[C:12]([O:36][CH3:37])[C:11]=4[C@@:6]2([CH3:38])[O:5][CH2:4][C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].[Na].C1C2C(=CC=CC=2)C=CC=1.[Cl-].[NH4+]>C1COCC1.C(O)C>[CH3:37][O:36][C:12]1[C:11]2[C@@:6]3([CH3:38])[O:5][CH2:4][CH2:3][N:2]([CH3:1])[C@@H:7]3[CH2:8][C:9]3[C:10]=2[C:15]([NH:16][CH:17]=3)=[CH:14][CH:13]=1
Reactant: COc1ccc2c3c(cn2S(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)C[C@H]2N(C)C(=O)CO[C@]2(C)c13
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: c1ccc2ccccc2c1
Product: COc1ccc2[nH]cc3c2c1[C@@]1(C)OCCN(C)[C@@H]1C3
Temperature: 0 °C
Yield: 27 %

Procedure:
To a solution of trans-4,6,6a,7,9,10a-hexahydro-7-methyl-10a-methyl-1-methoxy-4-(2,4,6-triisopropylphenylsulfonyl)-indolo[3,4-gh][1,4]benzoxazin-8-one (1.9 g, 3.4 mmol) in THF (30 ml) was added, while stirring under ice-cooling, LAH (3 equivalents). The mixture was heated for 3 hours under reflux. After completion of the reaction, ethanol was added to the reaction mixture, and the mixture was then added to an ice-cooled saturated aqueous solution of sodium sulfate. The mixture was subjected to extraction with ethyl acetate. The extract was washed with an aqueous saline solution, and was then dried (anhydrous sodium sulfate). The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with ethyl acetate to leave 700 mg of a residual substance. To a solution of this residual substance in THF (10 ml) was added, at room temperature in argon streams, a solution of 0.5M naphthalene sodium in THF (10 equivalents). The mixture was stirred for 10 minutes at room temperature, and was added to an ice-cooled saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saline solution, which was dried (anhydrous sodium sulfate). The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with ethyl acetate to afford 250 mg (27%) of the title compound as crystals, m.p.200°-202° C. (isopropyl ether-ethyl acetate).
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([CH3:9])[N:6]=[CH:5]1)(=O)C.[O:10]1CC[CH2:12][CH2:11]1>>[C:11]([C:8]1[NH:4][CH:5]=[N:6][C:7]=1[CH3:9])(=[O:10])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(=O)n1cnc(C)c1
Product: CC(=O)c1[nH]cnc1C
Yield: 38 %

Procedure:
A solution of 5.0 g (40.3 mmol) of 1-acetyl-4-methylimidazole in 700 ml of dry tetrahydrofuran was photolyzed in a quartz flask with a short wave ultraviolet light source (254 nm) for 24 hours. The tetrahydrofuran solution was concentrated in vacuo to give an oil which was chromatographed on silica gel using 5% methanol in chloroform as eluent to give 1.91 g (38%) of 5-acetyl-4-methylimidazole as a white solid, mp 140°-142°. nmr (CDCl3 /D6DMSO) (δ): 7.45 (s, 1H); 2.52 (s, 3H); 2.48 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1csc(CBr)n1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A solution of ethyl 2-methyl-4-thiazolecarboxylate [JCS 1946, 87, E. R. H. Jones, F. A. Robinson, M. N. Strachan] (5.0 g, 29.2 mmol) in CCl4 (30 ml) was treated with N-bromosuccinimide (5.2 g, 29.2 mmol) and benzoylperoxide (0.03 g). The reaction was heated to reflux while irradiating with a strong lamp for 21/2 hours. The reaction mixture was allowed to cool to ambient temperature, filtered and evaporated. The residue was purified by chromatography (eluant: CH2Cl2) to obtain ethyl 2-bromomethyl-4-thiazolecarboxylate (2.27 g, 31%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]([Cl:16])([Cl:15])[C:11](=N)OC>C(O)(=O)C>[Cl:9][C:10]([Cl:16])([Cl:15])[C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
8.6 Grams of an o-phenylenediamine compound [compound (204)] of the formula (XII) in which X is H and Z is OCF2O was dissolved in 80 ml of acetic acid. 8.7 Grams of methyl trichloroacetoimidate was added thereto at room temperature. The resulting mixture was stirred for 20 minutes. The reaction solution was poured into ice water, and precipitated crystals were filtered off. The crystals were dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 5.35 g of a 2-(trichloromethyl)benzimidazole compound [compound (104)] of the formula (XI) in which X is H and Z is OCF2O.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[NH2:38][OH:39].Cl>O>[OH:36][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:38][OH:39])=[CH:8][C:7]=1[S:9]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)NO)ccc2O)c(OCC(=O)O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
Method 2) To a stirred solution of 117 g of sodium[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate in 1.17 L of water was added 56 g of 50% aqueous hydroxylamine solution at room temperature, and the mixture was stirred at 70° C. for 4 hours. To the reaction mixture was added dropwise 1 mol/L hydrochloric acid at room temperature, and the mixture was stirred at the same temperature over night. The obtained solid was collected by filtration to give 110 g of [4-[2-[2-hydroxy-5-(N-hydroxy-carbamimidoyl)benzenesulfonylamino]ethyl]-2′-methane-sulfonylbiphenyl-3-yloxy]acetic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[CH:17][CH:16]=[C:15]([I:23])[CH:14]=1>>[I:23][C:15]1[CH:14]=[CH:13][C:18]([S:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:20])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(I)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and pipsyl chloride as described in the synthetic METHOD B to give a white solid (47.0 mg) with purity >90%. LCMS (pos) m/z 453.0.
Reaction SMILES: C([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=2)[CH:8]=1)=[O:6])(C)C.Br[C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=1.BrC1C=NC2C(C=1)=CC=CC=2>>[O-:33][N+:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[C:24][C:20]2[CH:19]=[C:18]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][N:11]=4)[C:16](=[O:17])[C:7]([C:5]([NH2:4])=[O:6])=[CH:8]3)[CH:23]=[CH:22][CH:21]=2)[CH:28]=1
Reactant: C#Cc1cccc(-n2cc(C(=O)NC(C)C)c(=O)c3cccnc32)c1
Reactant: [O-][n+]1cccc(Br)c1
Agent: Brc1cnc2ccccc2c1
Product: NC(=O)c1cn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of example 19, but substituting the 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide from Step 3 for N-Isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and 3-bromopyridine N-oxide for 3-bromoquinoline, the 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide was obtained as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].CCN(CC)CC.[NH2:27][CH2:28][CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:27][CH2:28][CH2:29][C:30]2[N:34]=[CH:33][NH:32][CH:31]=2)[N:14]=1)[C:11]#[N:12]
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Reactant: NCCc1c[nH]cn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CC(c1ccnc(NCCc2c[nH]cn2)n1)c1nc2ccccc2s1
Temperature: 70 °C
Reaction time: 72 h
Yield: 37.2 %

Procedure:
To a suspension of 1 (0.1 g, 0.35 mmol) in dry EtOH (3 ml) was added Et3N (0.05 ml, 0.35 mmol) and histamine (0.078 g, 0.70 mmol). After sonication, the yellow solution was shaken at 70° C. for 3 days. The yellow precipitate formed was filtered off and washed with H2O (2×) then EtOH (3×) and dried under vacuum at 40° C., affording 47 mg (37%) of the title compound as a bright yellow powder: mp 257-258° C., 10 was taken up in a mixture of DCM/TFA. The yellow fluffy solid formed by addition of ether was filtered off, washed with ether (3×) then dried under vacuum at 40° C., affording 36 mg (29%) of the title compound as a yellow powder: mp 247-249° C., MS: 362.0 (M+1); HPLC (Conditions a, 265 nm): 98%, rt. 2.87 min; 1H NMR (DMSO-d6): δ 14.25 (br s, 2H, exchangeable), 11.05 (br s, 1H, exchangeable), 9.03 (s, 1H), 7.94-7.87 (m, 1H), 7.74-7.71 (m, 2H), 7.57-7.52 (m, 2H), 7.42-7.37 (m, 1H), 7.24-7.19 (m, 1H), 6.40 (d, J=7.1 Hz, 1H), 3.97-3.55 (m, 3H), 3.11-3.05 (m, 2H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:22]=[CH:21][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]2[CH2:51][O:50]2)=[CH:43][CH:42]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:50][C@H:49]([CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([OH:40])=[CH:42][CH:43]=1)[CH2:51][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(N)=O)CC2)cc1
Solvent: O=CO
Product: NC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 12.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-1-piperidinecarboxamide formate (0.76 g, 2.37 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.817 g, 2.02 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.175 g, 0.26 mmol).
Reaction SMILES: [Br-].Br[C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][CH:8]=1.O.O1[CH2:19][CH2:18][CH2:17]C1>[Cl-].[Zn+2].[Cl-].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>[CH:17]1([C:3]2[CH:4]=[CH:5][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][CH:8]=2)[CH2:18][CH2:19]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1ccc(C2CC2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of zinc chloride (27 g) in tetrahydrofuran (300 mL) was cooled to 0° C. in the presence of a nitrogen gas, and a 1 M solution of cyclopropanemagnesium bromide in tetrahydrofuran (186 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was cooled to 0° C. Dichlorobis(triphenylphosphine)-palladium(II) (3.26 g) and a solution of ethyl 5-bromopyridine-2-carboxylate (21.4 g) in tetrahydrofuran (100 mL) were sequentially added, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give ethyl 5-cyclopropylpyridine-2-carboxylate (15.5 g, 87%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:38]=1[O:47][CH3:48]>>[CH3:44][O:43][C:41](=[O:42])[C:40]1[CH:45]=[CH:46][C:37]([CH2:36][O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:38]([O:47][CH3:48])[CH:39]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Product: COC(=O)c1ccc(COCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(OC)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c) and methyl 4-(bromomethyl)-3-methoxybenzoate (commercially available), to give the compound as light yellow solid (73%). MS (Turbo Spray): m/z=569.4 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:15][S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.O.O1CCOCC1.C(O)C>[OH-].[K+]>[CH2:8]([S:7][CH2:6][CH:5]([CH2:15][S:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:24])=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(CSCc1ccccc1)CSCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)C(CSCc1ccccc1)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
3-Benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid ethyl ester (1.589 g, 4.41 mmol) in a mixture of potassium hydroxide (1N, 7 mL), water (3 mL), dioxane (30 mL) and ethanol (10 mL) was stirred at room temperature for 18 hours. The solvents were removed form the reaction mixture by rotary evaporation at reduced pressure and the residue was dissolved in water and washed with ether. The aqueous layer was cooled on ice, acidified to pH 2 and the product extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give 3-benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid (1.293 g, 88%).