Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][CH2:20][CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Si:11]([O:18][CH2:19][CH2:20][CH:21]=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC=O

Procedure:
To a solution of anhydrous dimethylsulfoxide (0.05 mole) in anhydrous methylene chloride (100 ml) cooled to 0° C. under nitrogen with stirring is added a solution of oxalyl chloride (0.05 mole) in anhydrous methylene chloride (100 ml). After stirring for 15 minutes, a solution of 1-tert-Butyldimethylsilyloxy-3-hydroxypropane (0.04 mole) in methylene chloride (150 ml) is added over a period of 30 minutes. Then the reaction is quenched by adding triethyl amine (1 mole) slowly. The reaction mixture is diluted with ethyl acetate (200 ml), washed with water (75 ml), brine (75 ml), dried and concentrated. The product is used as such in the subsequent condensation step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:23]=[CH:22][C:9]([C:10]([NH:12][C:13]3[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[F:21])=O)=[CH:8][C:7]=2[F:24])[CH2:3][CH2:2]1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:23]=[CH:22][C:9]([C:10]3[O:19][C:18]4[CH:17]=[C:16]([OH:20])[CH:15]=[C:14]([F:21])[C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:24])[CH2:3][CH2:2]1
Reactant: O=C(Nc1c(O)cc(O)cc1F)c1ccc(OCC2CC2)c(F)c1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluoro-N-(2-fluoro-4,6-dihydroxyphenyl)benzamide (2.29 g), hexachloroethane (4.04 g) and triphenylphosphine (4.48 g) in acetonitrile (50 mL) was added triethylamine (2.86 mL) at 0° C., and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 1 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (110 mg). 1H NMR (300 MHz, CDCl3) δ 0.37-0.45 (2H, m), 0.65-0.74 (2H, m), 1.24-1.44 (1H, m), 3.97 (2H, d, J=7.2 Hz), 5.26 (1H, d, J=3.4 Hz), 6.97-7.10 (2H, m), 7.38 (1H, dd, J=8.5, 1.3 Hz), 7.87-7.98 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(Cc1c[nH]c2c(-c3cccs3)cccc12)NC(=O)OC(C)(C)C
Yield: 31.3 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (437 mg, 1.00 mmol) in dimethylformamide (6 mL) is added triethylamine (0.18 mL, 1.30 mmol), tetrakis(triphenylphosphine)-palladium (46 mg, 0.0401 mmol) and 2-thiopheneboronic acid (167 mg, 1.30 mmol). The mixture is refluxed for 22 hours, then cooled and diluted with brine and ethyl acetate. The organic phase is washed 7 times with brine. The organics are dried over anhydrous sodium sulfate, filtered and then evaporated in vacuo. The residue is purified using silica gel chromatography (hexane/20% ethyl acetate, hexane gradient elution) to give 116 mg of [1,1-Dimethyl-2-(7-thiophen-2-yl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (31%). FDMS m/e=371 (M++1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2][CH:3](C)C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCCC>>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2][CH3:3]
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Agent: O=Cc1c(O)ccc2ccccc12
Solvent: CCCBr
Product: CCCOc1ccc2ccccc2c1C=O

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 1-bromopropane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(F)(F)CCc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3CC(F)(F)CCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 5-(4-bromo-phenyl)-4-(2,2-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1I.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C1COCC1.C(OCC)(=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.[Cu]I>[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccc(I)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 2.89 ml (20.7 mmol, 5.0 eq.) of triethylamine, 2.99 g (4.1 mmol) of 2-bromo-4-chloro-1-iodobenzene and 489 mg (4.97 mmol, 1.2 eq.) of ethynyl(trimethyl)silane were added successively to a solution of 73 mg (0.10 mmol, 0.025 eq.) of bis(triphenylphosphine)palladium(II) chloride and 20 mg (0.10 mmol, 0.025 eq.) copper(I) iodide in 27 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was then diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. After addition of ethyl acetate/water and phase separation, the organic phase was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 3.21 g (quant.)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:12][C@@H:11]2[C:33]([O-:35])=O)=[O:8])=[CH:4][CH:3]=1.[Li+].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:49][NH:50][CH2:51][CH2:52][OH:53]>C1COCC1.CN(C=O)C>[OH:53][CH2:52][CH2:51][N:50]([CH3:49])[C:33]([C@@H:11]1[C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])[CH2:12]1)=[O:35]
Reactant: CNCCO
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](C(=O)[O-])C1)Nc1ccc(-n2ccccc2=O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(CCO)C(=O)[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
Lithium (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylate (example 41; 0.09 g) is dissolved in THF/DMF (1:1; 3 ml) and CDI (0.083 g) is added. The mixture is stirred for 1 h at 25° C., after that 2-(methylamino)-ethanol (0.03 ml) is added. The reaction mixture is stirred for 18 h at 25° C. and evaporated to dryness followed by flash chromatography over silica gel using DCM/MeOH/NH3 as eluent to yield 0.033 g (33.4%) (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylic acid (2-hydroxy-ethyl)-methyl-amide. White solid. MS 576.5 [M+H+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH2:7].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28]([NH:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1nccs1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1nccs1
Yield: 71 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use thiazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 71% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (t, J=5.9 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.70 (d, J=3.3 Hz, 1H), 7.60 (d, J=3.3 Hz, 1H), 7.45-7.33 (m, 5H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.66 (d, J=5.9 Hz, 2H), 2.56 (m, 3H); MS (ES+) m/z 439.1 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16]Br)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH:27]([CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:27]([N:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH:15]([OH:18])[C:13]2[N:14]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][CH:12]=2)[CH3:39])=[CH:30][CH:31]=1)([O:37][CH3:38])=[O:36]
Reactant: O=C(Nc1nc(C(=O)CBr)cs1)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C)NCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(C)N(Cc2ccccc2)CC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.5 g (0.011 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolved in 20 ml of dimethylformamide and added dropwise to a stirred solution, at room temperature, of 2.6 g (0.092 mol) of N-benzyl-2-(4-carbomethoxyphenyl)-1-methylethylamine and 1.1 g (0.011 mol) of triethylamine dissolved in 40 ml of dimethylformamide. After 1.5 hours ice/water is added, and the mixture is extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated. The resulting amino-ketone is taken up in 100 ml of methanol and at room temperature, 0.6 g of sodium borohydride is added. After 1 hour the mixture is evaporated to dryness, water is added, and hydrochloric acid is used to acidify. After 10 minutes the mixture is made alkaline with ammonia and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using toluene/ethyl acetate=8:2 as eluant.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11](Cl)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:12]=[C:11]([O:23][C:18]2[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=2)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(Oc2ccc(F)c(F)c2)nc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of ethyl 2,6-dichloro-5-fluoronicotinate (20 g, 84 mmol) and 3,4-difluorophenol (10.93 g, 84 mmol) in acetonitrile (200 mL) was added potassium carbonate (20.90 g, 151 mmol). The reaction mixture was stirred at 80° C. for 2 hr. and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with Hex/EtOAc (10:1) to give ethyl 2-chloro-6-(3,4-difluorophenoxy)-5-fluoronicotinate (23.5 g, 80%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][S:2]([CH3:1])(=[O:4])=[O:3])[CH:31]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulphonyl chloride (0.16 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-aminobenzamide (0.765 g), pyridine (0.29 ml) and methylene chloride (30 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. A second portion (0.158 ml) of methanesulphonyl chloride was added and the resultant mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was washed with water, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was dried under vacuum at 60° C. There was thus obtained the title compound (0.97 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.03 (s, 3H), 3.2 (t, 4H), 3.74 (t, 4H), 7.17 (m, 1H), 7.23 (d, 1H), 7.4 (m, 5H), 7.59 (m, 1H), 7.7 (d, 1H), 7.8 (m, 2H), 9.93 (d, 2H), 10.14 (s, 1H); Mass Spectrum: M+H+ 509.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Br:18])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:27]([NH2:30])[C:28]#[CH:29].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Br:18])[C:12]([NH:30][CH2:27][C:28]#[CH:29])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)cc(OCc2ccccc2)c1Br
Reactant: C#CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)c1cc(OC)c(Br)c(OCc2ccccc2)c1
Yield: 84.7 %

Procedure:
To a suspension of 3-(benzyloxy)-4-bromo-5-methoxybenzoic acid (2.0 g, 5.93 mmol) and 4 drops of DMF in DCM (40 mL) was slowly added oxalyl chloride (0.57 mL, 6.52 mmol). After three hours the solvent was removed and the residue was redissolved in DCM (10 mL). To this solution was slowly added a mixture of propargylamine (0.46 mL, 7.12 mmol) and triethylamine (2.5 mL, 17.8 mmol) in DCM (2 mL). After 30 minutes the solution was diluted with ether, washed with water (2×), 1 M hydrochloric acid (2×), water, saturated sodium bicarbonate, brine, then dried over magnesium sulfate and concentrated to a yellow solid. The solid was triturated with diethyl ether and dried under vacuum to provide 3-(benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide (1.88 g) as an off-white solid. MS=374.0 (M+1).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[CH2:16]2)=[CH:11][CH:10]=1.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>O>[CH2:44]([O:43][C:41]([CH2:40][CH2:39][CH2:38][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:16][C:17]3[C:22](=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[C:19]([O:28][CH3:29])[C:18]=3[O:30][CH3:31])[CH2:23]2)=[CH:13][CH:14]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)C1(c2ccc(O)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
Sodium hydride (60% oily, 9.8 mg, 0.244 mmols) was added to a DMF (2 ml) solution of ethyl 2-(4-hydroxyphenyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (81.5 mg, 0.203 mmols), with cooling with ice. The reaction mixture was stirred at room temperature for 30 minutes, and ethyl 4-bromobutyrate (0.0600 ml, 0.406 mmols) was dropwise added thereto at room temperature, and stirring was continued for 3 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain the entitled compound (85.1 mg) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CCOCC>[CH3:24][S:25]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:27])=[O:26]
Reactant: CCCCC[C@@H](CCCO)OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC[C@@H](CCCOS(C)(=O)=O)OC1CCCCO1
Reaction time: 4 h

Procedure:
A mixture of (4S)-4-(2-tetrahydropyranyloxy)-1-nonanol (29.2 g., 0.12 mole) and pyridine (20 ml.) is cooled to 5° by means of an ice bath. Methanesulfonyl chloride (17.2 g., 0.15 mole) is added dropwise during 20 minutes and the mixture is stirred 4 hours with ice bath cooling. The mixture is then taken up in ether, washed with 4 portions of water and with brine and dried over sodium sulfate. The ether is distilled on the rotary evaporator to leave as a residual oil crude (4S)-1-methylsulfonyloxy-4-(2-tetrahydropyranyloxy)-nonane.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([CH2:41][O:42][C:43]2[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C:2]3[CH:35]=[CH:34][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[CH:22][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:4][CH:3]=3)[CH:46]=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: OB(O)c1cccc(OCC2CCCC2)c1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4cccc(OCC5CCCC5)c4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-(cyclopentylmethoxy)phenylboronic acid (44 mg, 0.2 mmol, prepared according to general procedure H) to give 5-{-4-[2-(3′-cyclopentylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[N:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH2:53]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[N:51]=[CH:50][C:49]([N:52]3[CH2:53][CH2:54][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:56][CH2:57]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 95 °C
Yield: 63.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 199e (287.4 mg, 0.60 mmol), 339c (145 mg, 0.30 mmol), Pd(dppf)Cl2 (24.5 mg, 0.030 mmol), K3PO4 (127.2 mg, 0.60 mmol), sodium acetate (49.2 mg, 0.60 mmol), water (0.50 mL), and acetonitrile (10 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 95° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 339d as a yellow solid (140 mg, 61%). MS-ESI: [M+H]+ 737.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].N1C=CC=CC=1>ClCCl>[CH2:20]([NH:22][C:23]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc2ccc(-c3cc(F)ccc3C)cc2cn1
Temperature: 40 °C

Procedure:
A mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (51.3 mg, 203 μmol) and ethyl isocyanate (20 uL, 0.26 mmol) in dichloromethane (2.0 mL) was heated at 40° C. for 4 days. The cooled mixture was treated with pyridine (20 uL, 0.25 mmol) and a further portion of ethyl isocyanate (20 uL, 0.26 mmol) at 40° C. for 24 h and concentrated in vacuo, and the residue purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (54.6 mg, 83%). 1H NMR (400 MHz, DMSO) δ 9.07 (s, 2H), 8.09 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.37 (t, J=7.2 Hz, 1H), 7.20-7.12 (m, 2H), 7.06-7.00 (s, 1H), 3.19 (dq, J=7, 7 Hz, 2H), 2.25 (s, 3H), 1.10 (t, J=7.2 Hz, 3H). LCMS (Method E): RT=4.885 min, M+H+=324.1.
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[S:8]([C:2]1([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: CNC
Product: CN(C)S(=O)(=O)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N,N-dimethyl-2,4-dichlorothiazole-sulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with 45% strength dimethylamine solution. Following recrystallization from petroleum ether/acetone 6:1, 21.7 g of product were obtained (83% of the theoretical yield), m.p.: 89°-90° C.