Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:12]=[N:13][C:14](I)=[N:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.[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>[Br:10][C:11]1[CH:12]=[N:13][C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][CH:16]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cnc(-c2ccccc2)nc1
Reaction time: 18 h
Yield: 50 %

Procedure:
To a degassed solution of phenylboronic acid (8.93 g, 73.22 mmol, 1.0 equiv; commercially available), 5-bromo-2-iodo-pyrimidine (20.86 g, 73.22 mmol, 1.0 equiv; commercially available) and tetrakis(triphenylphosphine) palladium(0) (0.85 g, 0.73 mmol, 0.01 equiv) in toluene (180 mL) was added Na2CO3 (15.52 g, 146.45 mmol, 2.0 equiv), dissolved in water (60 mL), and the reaction mixture heated to reflux. After 18 h, tetrakis(triphenylphosphine) palladium(0) (0.42 g, 0.37 mmol, 0.005 equiv) was added and the reaction mixture heated for an additional time period of 24 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a sat. solution of NaCl (200 mL) with ethyl acetate (3×150 mL). The combined organic phases were dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with heptane/ethyl acetate (9:1) to provide 8.60 g (50%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(Cl)(Cl)Cl.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([C:29](Cl)=[O:30])[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=1)(=[O:18])=[O:17]>C(Cl)(Cl)Cl.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:29]([C:21]1[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=[C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])[CH:20]=1)=[O:30])[CH3:2]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: CCN1CCCC1CN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 66.1 %

Procedure:
82 g of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine, 600 ccm of chloroform and, gradually, at a temperature of from 5°-10° C.; 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask with an agitator and a thermometer. After the addition of a liter of water chloroform was distilled and then the remaining solution was filtered. The base was precipitated by the addition of 60 cm3 of 20% ammonia. The crystals formed were dried off, washed with water and then dried. 162 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 136°-137° C.; yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:31][CH2:32][OH:33])[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:30])[C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:33][CH2:32][CH2:31][C@:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:17]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)[CH2:10]1)(=[O:44])=[O:43]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
5.68 g (11 mmol) of the obtained alcohol form was dissolved in methylene chloride (60 mL) and 2.3 mL (16.5 mmol) of triethylamine was added thereto under a nitrogen atmosphere. 1.02 ml (13.2 mmol) of methanesulfonyl chloride was added to the mixture under ice-cooling and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=3/2) to obtain 6.09 g (yield: 93%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1>CO>[C:29]1([S:26]([N:13]([CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([CH3:35])[C:3]([OH:36])=[O:2])[CH:11]=[CH:10][CH:9]=2)[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)(=[O:28])=[O:27])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C(C)Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1
Solvent: CO
Product: CC(Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1)C(=O)O

Procedure:
The title compound was prepared following the method described in Example 1, Step C, from 3-(3-{[benzenesulfonyl-(4-pyrazol-1-yl-benzyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid methyl ester of Step E, except that the hydrolysis was performed in MeOH at reflux over 24 h. 1H NMR (400 MHz, CD3OD) δ 8.14 (m, 1H), 7.90 (m, 2H), 7.69-7.53 (m, 6H), 7.17 (m, 2H), 7.07 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.79 (s, 1H), 6.49 (m, 1H), 4.34 (s, 2H), 4.31 (s, 2H), 2.79 (m, 1H), 2.50 (m, 2H), 1.02 (d, 3H); MS 488 (M−1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[C:13]([NH2:15])[C:12]([Cl:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.Cl.[NH2:19][CH:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.[OH-].[Na+].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.O>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[CH:20]([NH:19][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([Cl:16])[C:13]([NH2:15])=[CH:14][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:21]2
Reactant: Nc1cc(OCC2CC2)c(C(=O)O)cc1Cl
Reactant: NC1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(OCC2CC2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.8 %

Procedure:
To a solution of 2-cyclopropylmethoxy-4-amino-5-chlorobenzoic acid (3.2 g; 0.0134 moles) in pyridine (15 ml), a solution of 3-aminoquinuclidine dihydrochloride (2.5 g; 0.0125 moles) and sodium hydroxide (0.5 g; 0.0125 moles) in water (15 ml) was added. To the resulting solution N,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added and the mixture stirred at room temperature for 20 hours. An additional amount of N,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added and the mixture stirred for a further 24 hours. The insoluble solid was filtered off, washed with water and the solvent removed in vacuo at a temperature between 30° and 45° C. The solid residue was taken up in water, made alkaline with sodium hydroxide and a solid precipitated which was filtered off and dried to give N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide (4.1 g) M.p 183°-185° C. after recrystallisation from acetonitrile.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][NH2:28])[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][NH:28][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.75 h

Procedure:
In a similar manner to Example 31, a solution of 0.85 part of phenylacetyl chloride in 10 parts by volume of diethyl ether is added to a mixture of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 1 part by volume of triethylamine and 25 parts by volume of chloroform. The whole mixture is stirred for 45 minutes, whereby 7-chloro-2-(2-phenylacetylhydrazino)-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals. Recrystallization from a mixture of dimethylformamide and water yields colorless fine prisms melting at 220° C to 221° C (effervescence).
Reaction SMILES: [O-]CC.[Na+].[H-].[Na+].[CH3:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([CH:9]([C:8](=[O:13])[CH3:7])[C:10](=[O:12])[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C(Cc1ccccc1)C(C)=O
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of sodium ethoxide (freshly prepared from sodium hydride (0.474 g, 19.8 mmol) and anhydrous ethanol (50 mL)) was added pentane-2,4-dione (6.00 g, 60.0 mmol). The resulting mixture was heated to 50° C. while a solution of benzyl bromide (3.42 g, 20 mmol) in ethanol (20 mL) was added over 30 minutes. The reaction was then heated to reflux. After 2 hours, the mixture was concentrated, and the residue was dissolved in ethyl acetate, washed three times with water, once with brine, dried (magnesium sulfate) and concentrated to afford an oil. Flash chromatography over silica (ethyl acetate/dichloromethane) afforded 3.13 g (82%) of a colorless oil. The proton spectrum showed the product exists as equal parts of the keto and enol tautomers: 1H NMR (CDCl3) δ 16.81 (s, 0.5H), 7.13–7.32 (m, 5H), 4.00 (t, J=7.6 Hz, 0.5H), 3.65 (s, 1H), 3.14 (d, J=7.6 Hz, 0.5H), 2.06–2.13 (m, 6H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1>CO.[Pd]>[F:15][C:14]1[CH:13]=[CH:12][C:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[OH:8]
Reactant: Cn1nccc1-c1ccc(F)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Cn1nccc1-c1ccc(F)c(O)c1
Yield: 91.9 %

Procedure:
A solution of 5-(3-benzyloxy-4-fluoro-phenyl)-1-methyl-pyrazole (which may be prepared as described in Description 82) (1026.5 mg, 3.64 mmol) in methanol (20 mL) was hydrogenated with an H-Cube using a 10% Pd/C (70 mm cartridge) at 50° C. and a flow rate of 1 mL/min. The eluent was concentrated in vacuo to give 2-fluoro-5-(2-methylpyrazol-3-yl)phenol (D83) (677.1 mg, 3.3469 mmol, 92.0% yield) as a colourless solid;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH:15]=C)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C[N+]1([O-])CC[O:21]CC1.I([O-])(=O)(=O)=O.[Na+]>O.C1COCC1.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH:15]=[O:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2]
Reactant: C=CCc1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Methyl 5-nitro-2-(prop-2-en-1-yl)benzoate (0.20 g, 0.90 mmol) in water (2 mL) and THF (5 mL) was added osmium tetroxide (0.57 mL 2.5% solution, 0.045 mmol) and NMO (0.16 g, 1.4 mmol). The mixture was allowed to stir at RT for 16 hours and monitored by TLC. The reaction was diluted with EtOAc, washed with NH4Cl and brine, and concentrated. The residue was redissolved in MeOH and water. After cooling the solution to 0° C., an aqueous solution of sodium periodate (0.39 g, 1.8 mmol) was dropped into the reaction and allowed to stir for 2 hours. The reaction was diluted with water, extracted with EtOAc, dried over sodium sulfate, and concentrated. The crude residue was purified by silica gel chromatography to provide Methyl 5-nitro-2-(2-oxoethyl)benzoate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.48 (S, 1H), 8.97 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 4.31 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]12.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:54])([F:53])[C:21]1[CH:22]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39](Cl)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>CS(C)=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39]([N:11]3[CH2:10][CH2:9][N:3]4[CH2:4][C@H:5]([CH2:7][OH:8])[NH:6][CH2:1][CH:2]4[CH2:12]3)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:22]=[C:21]([C:20]([F:54])([F:19])[F:53])[CH:26]=1
Reactant: OC[C@H]1CN2CCNCC2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C[C@H](CO)NCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 23 h

Procedure:
To a solution of (3R)-octahydro-2H-pyrazino[1,2-a]pyrazin-3-ylmethanol (D89, Mixture of diastereoisomers of unknown ratio, 83.5 mg, 0.496 mmol) in 1.6 mL of DMSO were added K2CO3 (78 mg) and 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (100 mg). The reaction was left at 150° C. for 23 h. It was checked by UPLC/MS, which showed a peak for the expected product at 0.71 min. (m/z=668 (M+1), 334 (M+2)/2). The solution was diluted with dichloromethane, extracted with water and dried (Na2SO4). The title ccompound obtained (113.5 mg) was taken to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][CH2:21][CH2:22][O:1][C:2]2[C:7]3[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Reactant: OCCCC1CCCC1
Product: CC1(C)OC(=O)c2c(OCCCC3CCCC3)cccc2O1

Procedure:
5-(3-Cyclopentyl-propoxy)-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and 3-Cyclopentyl-propan-1-ol under conditions analogous to example 51-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.39 (t, J=8.4 Hz, 1H), 6.57 (d, J=8.5 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.05 (t, J=7.0 Hz, 2H), 1.94-1.47 (m, 11H), 1.69 (s, 6H), 1.12 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)O1.[CH2:29]([O:36][C:37](=[O:48])[NH:38][C:39]1[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=1[CH2:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>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(Cl)Cl.CN(C=O)C>[CH2:29]([O:36][C:37]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH:16]=2)=[CH:41][C:40]=1[CH2:46][CH3:47])=[O:48])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCc1cc(Br)ccc1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Yield: 57.2 %

Procedure:
Potassium carbonate (215 mg, 1.55 mmol) the tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (I37) (160 mg, 0.517 mmol), benzyl(4-bromo-2-ethylphenyl)carbamate (I34) (182 mg, 0.543 mmol), PdCl2(dppf)-DCM solvate (22 mg, 5 mol %) and DMF (5 mL) were loaded into a Schlenk tube, and degassed with 3× vacuum/nitrogen cycles. The mixture was brought to 80° C. under nitrogen then after 18 hours cooled and poured into water (100 mL). DCM (75 mL) and brine (50 mL) were added, the aqueous phase was washed with further DCM (2×75 mL), and the combined DCM extracts washed with brine, dried and evaporated. Chromatography (40 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I39) (129 mg, 57% yield) as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.45-731 (m, 5H), 7.22 (dd, J=8.5, 2.1 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 6.48 (s, 1H), 5.99 (s, 1H), 5.21 (s, 2H), 4.06 (d, J=2.5 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 2.58 (q, J=7.6 Hz, 2H), 2.50 (s, 2H), 1.49 (s, 9H), 1.22 (t, J=7.6 Hz, 3H). LCMS Method C: rt 6.67 min; m/z 337.1 [M-Boc+2H]+, 381.1 [M-tBu+2H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum and the residue was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined, washed with brine and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (10/1) gave 480 mg (82%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.
Reaction SMILES: [OH-].[K+:2].[SH2:3].Cl[C:5]1[N:10]=[N:9][C:8](Cl)=[C:7]2[CH:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:6]=12.[SH-:22].[K+]>C(O)(=O)C.CO>[SH-:3].[K+:2].[SH:3][C:5]1[N:10]=[N:9][C:8]([SH:22])=[C:7]2[CH:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:6]=12
Reactant: Clc1nnc(Cl)c2cc(-c3ccccc3)ncc12
Reactant: S
Agent: [K+]
Agent: [OH-]
Agent: [SH-]
Solvent: CO
Solvent: CC(=O)O
Product: Sc1nnc(S)c2cc(-c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydrosulfide methanolic solution is prepared by reacting 7 parts by weight of potassium hydroxide, 150 parts by volume of methanol and hydrogen sulfide gas in accordance with the known method. 4.2 parts by weight of 1,4-dichloro-7-phenyl-pyrido[3,4-d]pyridazine is added to the potassium hydrosulfide solution, and the resulting mixture is stirred at room temperature for three hours. Methanol is evaporated under reduced pressure, and the residue is added to 50 parts by volume of water to obtain a solution. The solution is acidified by the addition of acetic acid to precipitate yellow crystals. The crystals are collected by filtration, washed with water and dried to obtain 1,4-dimercapto-7-phenyl-pyrido[3,4-d]pyridazine melting at 212° to 215°C (decomposition).
Reaction SMILES: [C:1]1([S:7][C:8]2[S:12][C:11]([CH2:13][NH:14][OH:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:20]=[C:21]=[O:22])(C)C>O1CCOCC1>[OH:15][N:14]([CH2:13][C:11]1[S:12][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[C:21]([NH2:20])=[O:22]
Reactant: ONCc1ccc(Sc2ccccc2)s1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(Sc2ccccc2)s1
Reaction time: 1 h

Procedure:
To a solution of N-(5-phenylthiothien-2-ylmethyl)-hydroxylamine (2.5 g) in dioxan (50 ml) at room temperature under nitrogen, was added trimethylsilylisocyanate (2.42 g) and the resulting solution stirred for 1 hour, quenched with saturated aqueous ammonium chloride, extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a white solid, recrystallised from ether/petroleum ether to give a white crystalline solid m.p. 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.C1COCC1.[OH-].[K+].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Reactant: C=CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)c1ccc(Cl)cc1Cl)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 108 %

Procedure:
1-(2,4-dichlorophenyl)-2-imidazolylethan-1-one (0.80 M) was dissolved with heating as necessary in a stirred mixture of THF (250 ml) and abs. ethanol (250 ml). After cooling to room temperature, potassium hydroxide (0.20 M) was added followed by a dropwise addition of ethyl acrylate (45.8 ml) via addition funnel over 10 min. A room temperature water bath was used to cool the exothermic reaction for the first 30 min. After stirring for 14-16 hours, the reaction was neutralized with gla. acetic acid (10 ml) and concentrated under reduced pressure. The residual dark reddish black slurry was dissolved in abs. ethanol (100 ml) and concentrated again under reduced pressure giving ethyl 5-(2,4-dichlorophenyl)-4-imidazolyl-5-oxopentanoate (2) in 108% yield. The crude material is contaminated with potassium salts and is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][N:13]([CH:15]=O)[CH3:14].COC(OC)N(C)C.S([O-])(O)(=O)=O.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](/[N:11]=[CH:12]/[N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1ccccc1Br
Agent: COC(OC)N(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1Br

Procedure:
The starting material, 2-bromobenzene-1-sulfonamide, is commercially available. Reaction of 2-bromobenzene-1-sulfonamide in a solvent such as DMF, with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by the addition of sodium hydrogen sulfate in water, yields 2-bromo-N-[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide. This compound is reacted with 4-methylphenylboronic acid to yield 4′-methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide, then the —(CH2)r-L1 moiety is added, for example, by a halogenation reaction, to form compound (1b).