Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH:14]2[N:27]([CH3:28])[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[N:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)=[CH:12][CH:13]=1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([C:43]([OH:45])=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:30][O:29][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C:11]3[N:10]=[CH:9][C:8]([NH:7][C:43]([C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:45])=[CH:13][CH:12]=3)[N:27]([CH3:28])[C:26]2=1
Reactant: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)c2ccc4c(c2)NC(=O)CS4)cn1)CO3

Procedure:
The titled compound is prepared as a light yellow lyophilizated powder following Scheme 5 and in analogy to Example 1 using [6-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid acid as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.[H-].[Na+].[Cl:20][C:21]1[C:26]2[N:27]=C(S(C)(=O)=O)[N:29]=[CH:30][C:25]=2[CH:24]=[CH:23][N:22]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:20][C:21]1[C:26]2[N:27]=[C:16]([NH:15][C:4]3[CH:5]=[CH:6][C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)=[CH:8][C:3]=3[O:2][CH3:1])[N:29]=[CH:30][C:25]=2[CH:24]=[CH:23][N:22]=1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2ccnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A solution of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 24 mg, 0.104 mmol) in THF (1 mL) was treated with sodium hydride (7 mg, 0.175 mmol) at 0° C. After stirring for 20 minutes at room temperature the mixture was cooled to 0° C. and 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 33 mg, 0.135 mmol) was added. The reaction was allowed to reach room temperature and stirred for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH (0.5 mL) were added and the resulting mixture stirred for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 80% EtOAc in cyclohexane to give the title compound (30 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:39])[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Yield: 53.4 %

Procedure:
The reaction of (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (233 mg, 552 μmol) with Lawesson's reagent (230 mg, 552 μmol) in 1,4-dioxane (15 ml) yielded the (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (129 mg, 53% yield) as a light yellow foam. MS (ISP): m/z=438.1 [M+H]+ and 440.2 [M+2+H]+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[OH:37].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:37][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: Oc1cc(F)ccc1F
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cc(F)ccc2F)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2,5-difluorophenol (0.23 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.29 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[N:18]([O-])=O.[Na+].[OH-].[Na+]>Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:17]=[N:18][N:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.51 g (6.02 mmol) 2-chloro-N4-(4-methoxy-phenyl)-pyrimidine-4,5-diamine in 75 ml 37% aqueous hydrochloric acid is treated with 852 mg (12.4 mmol) sodium nitrite. The mixture is stirred for 16 hours at room temperature. Aqueous sodium hydroxide is added to the reaction mixture to reach a neutral pH-value. Then the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated giving 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine as brown solid; HPLC/MS (A): 1.89 min, [M+H] 262;
Reaction SMILES: [Br:1][C:2](C)([CH3:6])[C:3](Br)=[O:4].Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOC(C)=O>[Br:1][CH:2]([CH3:6])[C:3]([NH:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)Br
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)NOCc1ccccc1
Yield: 53 %

Procedure:
Prepared in 53% yield (631 mg, 2.44 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide (1.0 g, 4.6 mmol) with O-benzylhydroxylamine hydrochloride (742 mg, 4.6 mmol) via general procedure A. Rf=0.28 (3:1, hexanes:EtOAc); mp=75.3-77.4° C.; 1H-NMR (500 MHz, CDCl3): δ 9.61 (br s, 1H), 7.44-7.26 (m, 5H), 4.90 (s, 2H), 4.31 (q, J=7.7 Hz, 1H), and 1.77 (d, J=6.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ 167.5, 134.8, 129.45, 128.9, 128.7, 78.3, 40.5, and 22.2; FT-IR (neat) 3110 (br), 2924, 2852, 1675 (s), 1508, 1495, 1453, 1364, 1188, 1038, 1023 cm-1;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:29](O)(=[O:32])[CH:30]=[O:31].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]2[O:11][C:30](=[O:31])[CH:29]([OH:32])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)cc2c1OC(=O)C2O
Yield: 99.6 %

Procedure:
18.7 g of 4-tert-butyl-2-(1-methyl-pentadecyl)-phenol (J.Amer.Chem.Soc., 74, 1952, 3599), 5.06 g of glyoxylic acid monohydrate and 0.05 g of p-toluenesulfonic acid are heated in 40 ml of 1 ,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 80 ml of water each time and freed of solvent using a rotary evaporator. 21.4 g of 5-tert-butyl-3-hydroxy-7-(1-methyl-pentadecyl)-3H-benzo-furan-2-one are obtained in the form of a yellowish oil. That yellowish oil is placed in 25 ml of toluene with 8 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 25 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 80 ml of toluene and, at room temperature, 7 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is isolated from the residue, in the form of a waxy red mass, by chromatography on silica gel (hexane/ethyl acetate 99:1). 4.1 g (20% of the theoretical yield, based on 4-tert-butyl-2-(1-methyl-pentadecyl)-phenol) of 5,5′-di-tert-butyl-7,7′-bis(1-methyl-pentadecyl)-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIIIa) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)=[CH:15][C:14](C(N2CCOCC2)=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NCCC1C2C(=CC=C([C:56]3[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=3)C=2)NC=1C1C=C(C)C=C(C)C=1.[NH4+].[OH-]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:29][CH:30]=2)=[CH:15][C:14]([C:56]2[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=2)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN)c3c2)C(C)(C)C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCNCCCCc4ccc(NS(C)(=O)=O)cc4)c3c2)C(C)(C)C1=O
Yield: 55 %

Procedure:
Reductive amination of 4-[4-(methanesulfonamido)phenyl] butyraldehyde (EXAMPLE 4) with 5-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one was carried out according to the method of Example 6.2, Step F, except that 90:10 CH2Cl2-MeOH was used to develop the preparative TLC plates, while 90:10:1 CH2Cl2-MeOH-concd. NH4OH was used to extract the product. This gave a 55% yield of very pale golden-yellow glass; homogeneous by TLC in 92.5:7.5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=628.5 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[S:9][C:10]([C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH2:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:25])[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:15])([CH3:4])([CH3:3])[CH3:2].[C:38](#[N:41])[CH:39]=[CH2:40]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[S:9][C:10]2[CH:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:28][CH2:40][CH:39]([C:38]#[N:41])[C:11]=2[C:12]=1[S:13](=[O:25])(=[O:26])[N:14]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CC#N
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Solvent: Cc1ccccc1C
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1c(NC(=O)OC(C)(C)C)sc2c1C(C#N)CCC2O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (5-[1-(t-butyldimethylsiloxy)vinyl]-3-{[2-(4-fluorophenyl)ethyl]methyl-sulfamoyl}-thiophene-2-yl)carbamic acid t-butyl ester (the compound of Preparation Example 113) (235 mg) and acrylonitrile (4 lpL) in xylene (1 mL) was irradiated with a 200 W microwave. After reacting at 100° C. to 150° C. for 30 minutes, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate) and (4-cyano-3-{[2-(4-fluorophenyl)ethyl]methylsulfamoyl}-7-t-butyl-dimethylsiloxy-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamic acid t-butyl ester (54 mg) was obtained as a mixture. In addition, the same reaction was carried out from the starting materials (293 mg), and the mixture (45 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH:14]=[O:15])[CH:8]=[N:9]2)[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][OH:15])[CH:8]=[N:9]2)[CH3:2]
Reactant: CCOc1cccc2ncc(C=O)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cccc2ncc(CO)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred solution of 5-ethoxyquinoline-3-carbaldehyde CCH 29158B (98 mg, 487 μmol) in THF (10 mL) at 0° C. in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (18 mg, 476 μmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 6 N aq. HCl solution (0.33 mL). After stirring for 15 min at that temperature, the mixture was basified by a 2 N aq. NaOH solution (1.0 mL). THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 41 mg (5-ethoxyquinolin-3-yl)methanol MDE 32076 as a colorless oil (41 mg, 41% yield).
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27].[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][CH:24]([C:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]=2[S:23][C:2]=1[C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:30])([F:42])[F:43])[CH:34]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CC(O)c1c(Br)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 85 °C
Yield: 61.3 %

Procedure:
To a solution of 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 0.143 mmol) in dioxane (2 mL) was added (3-(trifluoromethoxy)phenyl)boronic acid (58.9 mg, 0.286 mmol), Pd(PPh3)4 (10 mg) and aq. 2M K3PO4 (0.4 mL). The reaction was heated at 85° C. for 2 h then cooled to RT and filtered. The filtrate was diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 5:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 61.2% yield) as a solid. LCMS: [MH+-THP] 487 and TR=2.079 min.
Reaction SMILES: S(=O)(=O)(O)O.Cl[S:7]([C:10]1[C:11]([O:21][CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16])(=O)=O>C(OCC)(=O)C.[Zn]>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([O:21][CH3:22])[C:10]([SH:7])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(=O)O)cc1S
Temperature: 0 °C
Yield: 51 %

Procedure:
To 20 g of crushed ice were added 3.7 ml of concentrated sulfuric acid and 1.90 g of 5-chlorosulfonyl-2,4-dimethoxybenzoic acid. Under ice-cooling, 2.40 g of zinc powder was added, and the mixture was then heated under reflux. After completion of the reaction, the reaction solution was diluted with ethyl acetate and insoluble matter was removed by celite filtration. The thus obtained filtrate was extracted with ethyl acetate, washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was washed with diethyl ether to give 0.74 g of 2,4-dimethoxy-5-mercaptobenzoic acid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:37]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Carbon tetrabromide (78.1 g, 235.6 mmole) and triphenylphosphine (123.5 g, 471.2 mmole) were combined in 460 ml dichloromethane in a flame dried 1000 ml three neck round bottom flask under nitrogen at 0° C. The mixture was stirred 1 hour at 0° C. and was treated portionwise with 4-benzyloxybenzaldehyde (25 g, 117.8 mmole). The reaction was stirred 30 minutes at 0° C. and was washed successively with 1×100 ml water and 1×100 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were poured into 3 liters hexane. The supernatant was collected and the residue was dissolved in a minimum amount of dichloromethane. This solution was also poured into 3 liters hexane and the process was repeated one more time. The combined supernatants were filtered through a 125 ml plug of silica gel (230-400 mesh) in a 600 ml coarse filter funnel. The plug was washed with 1 liter 15% ethyl acetate/hexane and the combined eluents were concentrated in vacuo to provide 38.2 g (89%) of 2-(4-Benzyloxyphenyl)-1,1-dibromo-ethene as a white solid. Melting Point: 97°-98° C. The dibromo-olefin (20 g, 54.3 mmole) was dissolved in 200 ml dry tetrahydrofuran in a flame dried 500 ml three neck round bottom flask under nitrogen. The solution was cooled to -78° C. and was treated slowly dropwise with butyllithium (70 ml, 108.6 mmole). The reaction was stirred 1 h at -78° C. followed by 1 hour at 0° C. The mixture was cooled to -78° C. and was treated with methyl-chloroformate (4.6 ml, 60 mmole). The reaction mixture was stirred for 20 minutes at -78° C. and then for 1.5 hours at 0° C. The reaction was quenched with 1×100 ml 1:1 saturated ammonium chloride/saturated sodium chloride. The layers were separated and the aqueous layer was washed with 2×100 ml diethyl ether. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a red oil. The oil was crystallized and then recrystallized from hexane to provide 9.2 g (75%) of methyl-4-benzyloxyphenyl-propiolate as orange tinged flakes. Melting Point: 78° C.
Reaction SMILES: N1CCCCC1.[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].C(=O)=O.Cl>N1C=CC=CC=1>[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C

Procedure:
8.5 g of piperidine were added to 185.5 g (1 mole) of 2-chloro-5-nitrobenzaldehyde and 125 g (1.2 moles) of malonic acid in 400 ml of pyridine, and the mixture was stirred at 110° C. until the evolution of CO2 was complete (about 3 hours). The reaction mixture was then poured on to a mixture of 1 l of ice and 350 ml of concentrated HCl, a yellow solid being precipitated. The product was filtered off under suction, washed with water and dried to give 220 g (97% of theory) of the above compound of melting point 193°-196° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH2:14][O:13][CH2:12][CH2:11][C:10]=2[CH2:15]O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Br:17]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:15][C:10]1[CH2:11][CH2:12][O:13][CH2:14][C:9]=1[C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nccc1C1=C(CO)CCOC1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)n1nccc1C1=C(CBr)CCOC1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of (5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methanol (300 mg, 1.35 mmol) in DCM (5 mL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc=4:1) to give 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (360 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCOc1cccnc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (3.50 g, 36.8 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (1.16 g of an 80% dispersion in mineral oil, 38.6 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The mixture was then cooled to 0-5° C., and 1-chloro-4-iodobutane (9.67 g, 44.2 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 6.89 g (quantitative yield) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22].C(Cl)Cl.B(Br)(Br)Br.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22]
Reactant: COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Yield: 62 %

Procedure:
5.4 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acetamide was dissolved in 50 mol of methylene chloride, then, 4.7 g of boron tribromide was added under ice cooling. The mixture was stirred for 2 hours under the same temperature, conc. hydrochloric acid was added to the solution and the resulted mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate, concentrated, and the resulted crystal was washed with t-butyl methyl ether to obtain 3.2 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide.