Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([CH2:10][CH:11]([C:20]3[C:21](=[O:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24](=[O:27])[C:25]=3[CH3:26])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl>C(O)(=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([C:20]3[C:21](=[O:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24](=[O:27])[C:25]=3[CH3:26])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:31][CH:32]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CCCCC(Cc1ccc(-n2ccnc2)cc1)C1=C(C)C(=O)C(C)=C(C)C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(CCCCC(=O)O)Cc2ccc(-n3ccnc3)cc2)=C(C)C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
In acetic acid (35 ml) was dissolved 3.50 g (8.06 mmole) of methyl 6-[4-(1-imidazolyl)benzyl]-6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)hexanoate, and concentrated hydrochloric acid (16.1 ml) was added to the solution, followed by stirring at 100° C. for 1 hour. The solvent was distilled off, and acetone was added to the residue, followed by concentration under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with chloroform/methanol (6:1). The fractions containing the object compound were collected and concentrated under reduced pressure, and the residue was crystallized to give 2.94 g (87%) of 6-[4-(1-imidazolyl)benzyl]-6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)hexanoic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.S(Br)(Br)=O.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O-].[Na+].[H-].[Na+].NCCOC(O)C>CCOCC.CN(C=O)C.COCCOCCOC.CCCCCCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[O:9][C:8]([CH2:10][O:11][CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH2:22])=[CH:7][CH:6]=1
Reactant: NCCOCC[O-]
Reactant: OCc1ccc(CCCCl)o1
Agent: CC(O)OCCN
Agent: O=S(Br)Br
Agent: [H-]
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: COCCOCCOC
Product: NCCOCCOCc1ccc(CCCCl)o1
Reaction time: 7 h
Yield: 58 %

Procedure:
A solution of [5-(3-chloropropyl)-2-furyl]methanol (500 mg, 2.5 mmol) in ether (6 mL) was dried over 3 {acute over (Å)} molecular sieves. After the sieves were removed, pyridine (245 μL, 3.0 mmol) was added to the solution. Thionyl bromide (215 μL, 2.9 mmol) was added dropwise to the solution. After 7 hours of stirring, the solution was rapidly injected into a solution of sodium 2-[2-aminoethoxy]ethoxide (534 mg, 4.2 mmol) in DMF (3 mL). (Sodium 2-[2-aminoethoxy]ethoxide was previously prepared by adding 60% NaH dispersion (2.85 g, 0.07 mol) subsequently cleaned with heptane to a solution of 2-aminoethoxyethanol (5 g, 0.04 mol) in diglyme (10 mL), stirred for 5 hours, and evaporated.) After 2 hours the reaction was placed in the freezer. After 18 hours the reaction was partitioned between dichloromethane (DCM) (50 mL) and water (50 mL). Water layer was extracted with additional 30 mL DCM. The combined DCM layers were washed with water (30 mL). The DCM layer were extracted with diluted HCl (1N, 30 mL) followed by water (20 mL). The acidic aqueous solutions were adjusted to pH=10 with diluted sodium hydroxide and back extracted with 2×20 ml DCM. The DCM was washed with brine, dried with sodium sulfate, filtered, and evaporated to yield 380 mg (58% yield). Used without further purification. TLC: Rf 0.5 (IPA/NH4OH/water 8/1/1 exposed with ninhydrin solution) Mass spectrum, m/e Calcd for C12H21ClNO3+: 262.1 (100%), 264.1 (32%). Found: 262.6, 264.6.
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][OH:22]>C(O)CCC>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:20]([CH2:21][OH:22])=[N:24][N:25]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NNC(=O)CO
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Solvent: CCCCO
Product: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
1.1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed for 8 hours with 1.5 g of glycolic acid hydrazide in absolute butanol. The solvent is then distilled off and the residue recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol, melting point 219°-221° C.
Reaction SMILES: [CH2:1]([S:9]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:11]1([NH:17][S:18]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([S:9][N:17]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[S:18]([C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)(=[O:19])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCSCl
Reactant: O=S(=O)(NC1CCCCC1)c1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCSN(C1CCCCC1)S(=O)(=O)c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The resulting orange-red n-octyl chlorosulfide solution is added dropwise to a stirred solution of 77.5 grams of N-cyclohexyl benzothiazole-2-sulfonamide (0.26 mole) and 28 grams triethylamine (0.28 mole) in 300 ml anhydrous dimethylformamide at about 13°-17° C. over 80 minutes. After 90 minutes of stirring, the reaction mixture is poured into 2 liters of ice water. A muddy solid is obtained upon decanting the water. The solid is washed in 200 ml n-hexane and filtered by suction. 105 grams of light brownish white crystal is obtained.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[C:2]=[O:3].Br.Br.[C:16]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:16]([N:20]1[CH2:25][CH2:24][N:23]([C:2]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:3])[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N1CCNCC1
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Br
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NC(=O)N1CCN(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To an ice cold solution of methyl 2-isocyanatobenzoate (0.18 g, 1.0 mmol) in dichloromethane (3 mL) was added dropwise a solution of 1-tert-butylpiperazine dihydrobromid (0.28 g, 0.92 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.1 mmol) in N,N-dimethylformamide (5 mL). The reaction solution was stirred at room temperature for 1 h, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.28 g (95%) of a yellow oil.
Reaction SMILES: B.CC(=CC)C.[CH2:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:8]=[CH2:9].[OH-:28].[Na+].OO>O1CCCC1.O>[OH:28][CH2:9][CH2:8][CH2:7][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCc1ccc2ccccc2c1OCc1ccccc1
Reactant: [OH-]
Agent: B
Agent: CC=C(C)C
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of borane (1.0M in tetrahydrofuran; 100 mL, 0.100 mole) was treated at 0° with a solution of 2-methyl-2-butene (2.0M in tetrahydrofuran; 100 mL, 0.200 mole) over 40 minutes, and the resulting solution stirred at 0° for 2 hours. A solution of 2-(2-propenyl)-1-benzyloxynaphthalene (27.40 g, 0.100 mole) in dry tetrahydrofuran (50 mL) was added over 25 minutes, and stirring was continued for 40 minutes. Water (4.0 mL) was then added, followed by 3.0M aqueous sodium hydroxide (34 mL), followed by 30% aqueous hydrogen peroxide (34 mL). After the mixture was warmed to room temperature, it was extracted with ether. The residue was chromatographed with 1:1 ether/hexane and recrystallized (cyclohexane) to provide the title compound (16.10 g, 55%) as a white solid, mp 80°-81°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24](Br)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC(Br)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cncc(Br)c2)C1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
To a solution of 5-bromopyridin-3-ol (0.285 g, 1.64 mmol) in DMF (2.5 mL) was added K2CO3 (0.453 g, 3.28 mmol), followed by 3-bromo-azetidine-1-carboxylic acid tert-butyl ester (0.425 g, 1.8 mmol) in DMF (0.5 mL) and the reaction mixture was heated to 60° C. and stirred over night. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and the aqueous layer was extracted EtOAc (2×20 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (0.539 g, 100%) as a colorless crystalline solid. MS: 329.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)(=[O:5])=[O:4]>[Pd].COCCOCCOC>[CH3:1][N:2]([CH3:16])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: COCCOCCOC
Product: CN(C)S(=O)(=O)Cc1ccccc1N
Yield: 59.6 %

Procedure:
In a pressure bottle, a mixture of 116 g of the product of Example 2, 1400 ml of 2-methoxyethyl ether and 10 g of 10% palladium on carbon was shaken at 110° under 500 p.s.i. hydrogen until the hydrogen was no longer absorbed. The catalyst was filtered off and the filtrate stripped under reduced pressure to a volume of 200 ml. This residue was poured into 600 ml of ice and the precipitate filtered off and dried to give 84 g of crude product, m.p. 70°-78°. Recrystallization from ~600 ml of 1-chlorobutane gave 60.6 g of N,N-dimethyl-2-aminobenzenemethanesulfonamide, m.p. 92°-100°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[F:25])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:38]2[C:39]([C:44]3C=CC=CC=3F)=[N:40]OC=2C)=NC=1.C(N)(C)C>>[F:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:40][CH:39]([CH3:44])[CH3:38])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(C)cc3F)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Solvent: CC(C)N
Product: Cc1ccc(-c2noc(C)c2COc2ccc(C(=O)NC(C)C)cn2)c(F)c1
Yield: 42 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (90 mg, 42%) which was obtained as a white solid. MS: m/e=384.3 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[NH:16][CH2:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([CH2:34][CH2:33][CH2:32][CH2:31][Br:30])[CH2:15]3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CN(CCCCBr)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
A solution of 17β-N-t-butylcarbamoyl-6-azaandrost-4-en-3-one (373 mg. 1.00 mmol), in dimethylformamide is treated with sodium hydride (50 mg, 60%, 1.25 mmol) at 0° C. for 30 minutes before the addition of 1,4-dibromobutane (0.179 mL, 1.5 mmol). After 30 minutes further the reaction is poured into ice water and extracted with methylene chloride (3×10 mL), dried over Na2SO4, concentrated and filtered through a plug of silica with 1:1 methylene chloride/acetonitrile followed by 10% methanol/methylene chloride. The methanolic fractions are concentrated to give crude 17β-N-t-butylcarbamoyl-6-(4-bromobutyl)-6-azaandrost-4-en-3-one. This material is dissolved in toluene (5 mL) and dimethylformamide (1.5 mL), sodium iodide added and the mixture heated at reflux for 7 hrs. The reaction is cooled, water added, extracted with methylene chloride (3×20 mL), dried over Na2SO4, concentrated and chromatographed (50% ethyl acetate/hexane) to give 17β-N-t-butylcarbamoyl-6-azaandrost-4,6-butano-4-en-3-one as a white solid; yield: 150 mg (35%). Recrystallization from ethyl acetate/hexanes gives an analytical sample as white crystals; m.p. 173°-174° C. Anal. Calcd. for C27H42N2O2.1/4H2O; C, 75.29; H, 9.94; N, 6.50. Found: C, 75.21; H, 10.04; N, 6.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3=[CH:16][S:17][CH:18]=[C:13]3[N:12]=2)[CH:4]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:12]1[C:13]2=[CH:18][S:17][CH:16]=[C:14]2[N:15]=[C:11]1[S:10][CH2:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: COc1ccnc(CSc2nc3cscc3n2C(=O)OCc2ccccc2)c1
Yield: 106.9 %

Procedure:
1.4 g (5 mmol) of 2-(4-methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole were reacted in analogy to Example 15 with 0.8 ml (5 mmol) of benzyl chloroformate (90-95%). 2.2 g of oily crude product were obtained and were chromatographed on silica gel (35-70μ) with toluene/ethyl acetate (1:5). The product crystallized from diethyl ether. Melting point 102°-104° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(N[C@H]1CCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Li])CCC.C[Si](Cl)(C)C.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:19])[CH3:18]
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cscn1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncsc1C(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methylthiazole (log) in dry tetrahydrofuran (50ml) at -70° C. was stirred under a nitrogen atmosphere and n-butyllithium (2.5M solution in hexane, 44.4 ml) was added dropwise. After 30 minutes, trimethylsilylchloride (12.8 ml) was added and the reaction mixture was allowed to warm to room temperature. After 30 minutes the mixture was cooled to -70° C. and n-butyllithium (44.4ml) was added dropwise. After 30 minutes, acetophenone (12.9ml) was added dropwise and the mixture stirred at -70° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and aqueous sodium hydrogen carbonate was added. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were then worked up to afford the title compound as a white solid, m.p. 128.5-129.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 10.0 mg (0.025 mmol) of ethyl 4-[2-(1,1-dimethyl-3-(4-methylphenyl)-5-indenyl)ethynyl]benzoate (Compound 47) in 0.5 ml THF/H2O (3:1 v/v) was added 5.2 mg (0.12 mmol) LiOH H2O. After stirring at room temperature for 48 hours the solution was extracted with hexanes and the aqueous layer was acidified with saturated aqueous NH4Cl. Solid NaCl was added and the resulting mixture extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a colorless solid. 1H NMR (300 MHz, d6 -DMSO): δ 7.95 (2H, d, J=8.3 Hz), 7.65 (2H, d, J=8.3 Hz), 7.57 (2H, m), 7.49 (3H, m), 7.30 (2H, d, J=7.9 Hz), 6.61 (1H, s), 2.36 (3H, s), 1.36 (6H, s).
Reaction SMILES: C(CC#N)(=O)C1C=CC=CC=1.[NH2:12][C:13]1[S:21][C:16]2[CH2:17][NH:18][CH2:19][CH2:20][C:15]=2[C:14]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[CH2:31]([O:38][C:39](Cl)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[NH2:12][C:13]1[S:21][C:16]2[CH2:17][N:18]([C:39]([O:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[CH2:19][CH2:20][C:15]=2[C:14]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCNC2
Agent: N#CCC(=O)c1ccccc1
Product: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCN(C(=O)OCc1ccccc1)C2

Procedure:
Using the procedures in Examples 7 and 8, substituting p-fluorobenzoyl acetonitrile for benzoyl acetonitrile, 2-amino-3-(4-fluorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3 -c)pyridine was prepared. This compound was reacted with benzyloxycarbonyl chloride to yield the title compound as a solid (mp 90-92° C). 1H NMR (CDCl3) 1.96 (m, 2H); 3.45 (m, 2H); 4.45 (s, 2H); 5.15 (s, 2H); 6.71 (bs, 2H); 7.05-7.52 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.18 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.090 g, 48%). MS (ISP) 373.0 [(M+H)+]; mp 168.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[C:35]3[S:39][N:38]=[CH:37][N:36]=3)=[CH:28][C:27]=2[F:53])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=3[CH:24]=2)[CH:7]=1.[H-].[Na+].I[CH3:57]>CN(C)C=O.C(OCC)(=O)C.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[C:35]3[S:39][N:38]=[CH:37][N:36]=3)=[CH:28][C:27]=2[F:53])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([CH3:57])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:12]=3[CH:24]=2)[CH:7]=1
Reactant: CI
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(NC(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (1.09 g, 1.39 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (0.061 g of a 60% dispersion in mineral oil, 1.53 mmol) and the reaction mixture was stirred for 10 minutes at ambient temperature. Iodomethane (87 μL, 1.39 mmol) was added and the reaction mixture for stirred for 30 minutes at ambient temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and saturated aqueous ammonium chloride (10 mL). The organic phase was washed with water (2 5 mL) and brine (10 mL) dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-50% gradient of ethyl acetate in hexanes to afford tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-phenyl)benzo[d]isoxazol-3-yl)(methyl)carbamate as a colorless foam.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:19]I.[Al]>CC(C)=O.[Ag-]=O>[CH3:19][O:10][C:9](=[O:11])[C@@H:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: CI
Agent: O=[Ag-]
Agent: [Al]
Solvent: CC(C)=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 100.2 %

Procedure:
To a solution of Boc-Chg-OH (53 mg, 0.206 mmol) in acetone (3 mL) were added methyl iodide (195 μL, 3.1 mmol) and silver (I) oxide (53 mg, 0.229 mmol). The mixture was allowed to stir over night in a reaction flask that was covered with aluminium foil. Thereafter the solution was filtered through celite and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 15:1) provided methyl ester 54 (56 mg, 100%) as a colorless oil.