Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]([CH:42]=2)[C:30]([NH:32][C:33]2([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:35][CH2:34]2)=[O:31])=[CH:23][C:7]2[C:8]([C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[CH2:1]([N:3]([C:4]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]([CH:42]=2)[C:30]([NH:32][C:33]2([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:35][CH2:34]2)=[O:31])=[CH:23][C:7]2[C:8]([C:18]3[N:19]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:20]=[CH:21][N:22]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=1)[S:46]([CH3:45])(=[O:48])=[O:47])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNc1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3nccn3S(C)(=O)=O)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(6-(ethylamino)-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-5-yl)-2-methoxy-N-(1-(pyrimidin-2-yl)cyclopropyl)benzamide (40 mg, 0.068 mmol) in pyridine (3.0 mL) at room temperature was added DMAP (16.60 mg, 0.136 mmol) followed by methanesulfonyl chloride (7.94 μl, 0.102 mmol). The reaction mixture was stirred at rt overnight, and then diluted with water. The mixture was extracted with EtOAc, and the organic extract washed with brine, dried over Na2SO4 and concentrated to obtain the title compound as an off white solid. Yield: 45 mg (89%). LCMS: (ES+) m/z=745.2 (M+H)+; Column—ACE Excel 2 C18 (50×3.0 mm-2 μm); M phase A: 2% MeCN-98% H2O-10 mM NH4COOH; M phase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56]>ClCCl.CN(C=O)C>[CH3:15][C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:55](=[O:56])[C:54]3[CH:58]=[CH:59][CH:60]=[C:52]([O:51][C:50]([F:49])([F:61])[F:62])[CH:53]=3)=[C:5]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH:6]=2)[N:14]=1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CNC(=O)c3cccc(OC(F)(F)F)c3)c(NCC(=O)OCc3ccccc3)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of compound 58d (50 mg, 0.13 mmol), TEA (0.027 mL), HOAt (1.8 mg) and EDCI (37 mg, 0.19 mmol) in a mixture of dichloromethane (0.8 mL) and DMF (0.3 mL) was added 3-trifluoromethoxybenzoic acid (27 mg, 0.13 mmol). The resulting solution was stirred overnight at rt, and then concentrated. The residue was triturated with water, and then purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 58e (30 mg, 43%). ESI-MS m/e 541.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=O)[CH3:14])=[CH:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]([NH2:22])[CH3:14])=[CH:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc2c(F)cc(F)cc2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc2c(F)cc(F)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.3 %

Procedure:
The above ketone (760 mg, 3.689 mmol) was dissolved in methanol (40 ml). Then, ammonium acetate (2.841 g, 36.896 mmol), sodium cyanoborohydride (232 mg, 3.389 mmol) and molecular sieves (3 Å, 7.6 g) were added. The mixture was stirred at room temperature for two days. The solid was filtered and the filtrate was concentrated. The residue was dissolved in water and concentrated aqueous HCl was added dropwise until the pH≈2. The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other by-products. The water layer was basified to pH≈10 with aqueous sodium hydroxide (1M), and was extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to afford 290 mg of 1-(5,7-difluoro-naphthalen-2-yl)-ethylamine (38% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1.O>C(#N)C>[N+:19]([C:16]1[S:15][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
To a solution of piperazine (18.2 g) and potassium carbonate (12.6 g) in acetonitrile (150 ml) was added 2-bromo-5-nitrothiazole (14.7 g) at 40° C. and the mixture was stirred at 60° C. for 40 min. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (11.2 g). The obtained brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (4.8 g) as yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH:34]([CH3:38])[C:35]([OH:37])=[O:36]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH:34]([CH3:38])[C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: CC(C(=O)O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 40.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.73 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.34 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])=[CH:27][CH:28]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1
Reactant: O=C(Cl)C1CCCC1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of (S)-2-[5-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5111, Example 111, 0.05 g, 0.12 mmol), Cyclopentanecarbonyl chloride (0.015 mL), and TEA (0.018 mL) in dichloromethane (3 mL) was stirred at 0° C. for 20 min. then was quenched with water. The mixture was concentrated in vacuo and the resulting residue was dissolved in DMF (5 mL) and water (0.5 mL) then purified by reverse phase prep. LC/MS to furnish the desired product; MS: 519.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:27])=[C:21]([O:25][CH3:26])[CH:22]=[C:23]([OH:24])[C:9]=2[CH2:8][S:7][CH2:6]1)=O>CO.C(N)C=C>[CH2:16]([NH:17][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:27])=[C:21]([O:25][CH3:26])[CH:22]=[C:23]([OH:24])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:2])[CH:15]=[CH2:14]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCC(=S)N1
Solvent: C=CCN
Solvent: CO
Product: C=CCNC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCC(=S)N1
Temperature: 50 °C
Yield: 147.5 %

Procedure:
A solution of 124 mg of (R)-15-hydroxy-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclo-tridecine-4-carboxylic acid methyl ester in a mixture of 1.5 ml of methanol and 1.5 ml of allylamine was heated to 50° C. for 2.5 h. The solution was evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:1, v/v) as eluent, and the purified product was crystallized from ethyl acetate/hexane to afford 97 mg of (R)-15-hydroxy-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid allylamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][C:18]=1[O:29][CH:30]([CH3:32])[CH3:31].[Li]CCCC.CCCCCC>C1COCC1>[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:22])=[CH:19][C:18]=1[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: CON(C)C(=O)c1ccc(F)c(OC(C)C)c1
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -76 °C
Reaction time: 1.5 h

Procedure:
A 3-liter four neck round-bottomed flask (flame dried) was charged 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (72.88 g, 0.25 mol), 4-fluoro-3-isopropoxy-N-methoxy-N-methylbenzamide (60.39 g, 0.25 mol) and dry THF (700 mL) under N2. The solution was cooled to −76° C., and a solution of n-BuLi in hexane (2.5M, 100 mL, 0.25 mol) was drop-wise maintaining the reaction mixture temperature below −70° C. over a period of 40 min. The reaction mixture was stirred at −76° C. for 1.5 h then quenched with 1N HCl (500 mL). The mixture was concentrated in vacuo to half the volume and was partitioned between EtOAc and H2O (v/v 1:0.3, 1 L). The organic phase was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic extracts were washed with brine and then concentrated in vacuo to give a yellow oil which was purified by column chromatography using CH2Cl2 in hexanes (0% to 20%) to give (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone as a colorless oil contaminated with a by-product (49.0 g, 50%). LC-MS (10-90% MeOH in H2O with 0.1% TFA in a 2-min gradient) 393.2 (M+H), retention time=2.15 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH:27](/B(O)O)=[CH:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH:27]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:9]=2)=[CH:6][CH:7]=1)=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(C=Cc3ccccc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.46 g, 3.2 mmol), trans-beta-Styreneboronic acid (0.7 g, 4.9 mmol), Na2CO3 (2M, 7 mL), and Pd(PPh3)2Cl2 (300 mg, 0.26 mmol) in toluene/ethanol (1:1, 20 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 6-(4-Styryl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as yellow solid in 68% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[I-].[K+].O>[CH2:2]([N:24]1[C:20](=[O:26])[CH2:21][CH2:22][C:23]1=[O:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CCC1=O
Temperature: 100 °C
Yield: 88.3 %

Procedure:
In a 500 ml flask equipped with a stirrer and a condenser were charged 30.6 g of 1-bromoctadecane, 10.0 g of succinimide, 13.9 g of potassium carbonate, 0.5 g of potassium iodide and 60 ml of DMF, and the mixture was stirred on an oil bath at 100° C. After cooling the reaction mixture to room temperature, it was poured into a large amount of distilled water, and the precipitated crystals were collected by filtration under reduced pressure and washed with distilled water. The residue was recrystallized from IPA to obtain 28.5 g of the title compound. Melting point: 76° C.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]4[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=4)=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(-n2c(CCC3CCCC3)nc3cccnc32)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(CCC4CCCC4)nc4cccnc43)cc2)cc1
Yield: 43.1 %

Procedure:
4-[2-(2-Cyclopentylethyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.22 g, 0.658 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.266 g, 0.656 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.209 g, 0.283 mmol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][NH:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([S:32]Cl)=[O:31]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][N:7]([S:32][C:30]([O:29][CH3:28])=[O:31])[C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: COC(=O)SCl
Reactant: O=C1CNC(c2cc(Cl)cc(Cl)c2)=NN1CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)SN1CC(=O)N(CC(F)(F)F)N=C1c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (110 mg, 0.34 mmol) dissolved in 5 mL tetrahydrofuran was added triethylamine (0.06 mL, 0.40 mmol) and methoxy-carbonylsulfenyl chloride (0.04 mL, 0.40 mmol). After 30 min, the reaction was quenched with water and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×5 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was subjected to flash column chromatography (10% ethyl acetate/hexanes) to afford 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4-(methoxycarbonylthio)-4,5-dihydro-1,2,4-triazin-6-one (60 mg, 43%) in 80% purity by LC.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:16][S:17]([O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23](Br)[C:22]=1[CH:30]=[O:31])(=[O:19])=[O:18]>CN(C=O)C.C(OCC)(=O)C.[Cu]>[CH3:16][S:17]([O:20][C:21]1[C:22]([CH:30]=[O:31])=[C:23]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[C:9]=2[O:10][CH3:11])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])(=[O:19])=[O:18]
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC
Reactant: COc1ccc(Br)c(C=O)c1OS(C)(=O)=O
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C=O)cc(OC)c(OC)c2OC)c(C=O)c1OS(C)(=O)=O
Temperature: 165 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
To a suspension of copper bronze (0.646 g, 10 mmol) in anhydrous DMF (2 mL) was added a solution of 2-bromo-3,4,5-trimethoxybenzaldehyde (0.80 g, 2.91 mmol) and 3-bromo-2-formyl-6-methoxyphenyl methanesulfonate (0.30 g, 0.97 mmol) in anhydrous DMF (1 mL) and the suspension was stirred at 165° C. for 3 hours. TLC indicated the presence of unreacted 3-bromo-2-formyl-6-methoxyphenyl methanesulfonate and a further portion of 2-bromo-3,4,5-trimethoxybenzaldehyde (100 mg) was added. After a further 1 hour at 165° C. the reaction was complete and the reaction mixture was cooled and diluted with ethyl acetate (20 mL). The resulting suspension was filtered through Celite® (3 g) and the filtrate concentrated in vacuo. The residue was chromatographed over silica gel (70 g), eluting with hexane-ethyl acetate (gradient 2:1 to 1:1), followed by crystallisation (ethyl acetate) yielded 2,6′-diformyl-4,2′,3′,4′-tetramethoxybiphenyl-3-yl methanesulfonate (180 mg, 44%); m.p. 130-131° C.; Elemental Analysis Found: C, 53.7; H, 4.8; S, 7.8 (C19H20O9S requires C, 53.77; H, 4.75; S, 7.56%); NMR Spectrum δH (300 MHz, CDCl3) 10.18 (1H, s, 2-CHO), 9.63 (1H, s, 6′-CHO), 7.36 (1H, s, 5′-H), 7.26 (1H, d, J 8.4 Hz, 6-H), 7.15 (1H, d, J 8.4 Hz, 5-H), 4.03 (3H, s, OCH3), 3.98 (3H, s, OCH3), 3.57 (3H, s, OCH3), 3.43 (3H, s, SCH3); NMR Spectrum δC (100 MHz, CDCl3) 50.2, 56.5, 56.9, 61.2, 61.5, 106.2, 116.8, 127.5, 130.0, 130.7, 131.0, 132.1, 139.8, 147.6, 151.1, 152.6, 154.0, 189.3, 190.5; νmax/cm−1 (thin film) 2934, 2843, 1701, 1682, 1588, 1561, 1480, 1371, 1336, 1285, 1169, 1111, 1072; m/z (ES) 447 (MNa+, 100%), 379 (5); Rf (hexane-ethyl acetate 1:2) 0.20.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].Cl.N1C=CC=CC=1.C(OCCO)C>>[OH:23][CH2:22][C:21]1[C:20]([CH3:27])=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(N)cccc1CO
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3C)c2cc1OC
Temperature: 139 °C
Yield: 91.6 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.151 g (1.1 mmol) of 3-amino-2-methylbenzyl alcohol, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 6 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.32 g (91.5%) of the desired product as light tan crystals. MP 123-125° C.;: mass spectrum (electrospray, m/e,): 349.9(M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]2)=[N:6][CH:7]=1.Br[C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1.OC(C1C=CN=C(C2C=NC(N3C4C(=CC=C(C(N5CCOCC5)=O)C=4)C(SC)=C3)=NC=2)C=1)(C)C>>[Cl:35][C:33]1[CH:32]=[CH:31][N:30]=[C:29]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:15]=4)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]3)=[N:4][CH:3]=2)[CH:34]=1
Reactant: Clc1ccnc(Br)c1
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: CSc1cn(-c2ncc(-c3cc(C(C)(C)O)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CS(=O)c1cn(-c2ncc(-c3cc(Cl)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Prepared from (1-(5-bromopyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)(morpholino)-methanone (0.5 g, 1.11 mmol) and 2-bromo-4-chloropyridine (0.23 g, 1.22 mmol) analogously to the experimental procedure for 289a). White solid. Yield: 61 mg (11% of theory)
Reaction SMILES: [NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43]>CN(C=O)C>[NH2:1][C:2](=[N:33][O:34][C:42]([O:44][CH2:45][CH:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)ON=C(N)c1ccc2c(c1)C(O[Si](C)(C)C(C)(C)C)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification.