Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]1([CH:7]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccccc1)c1cccc(N)c1)c1cccc(F)c1
Yield: 92.6 %

Procedure:
Following a procedure similar to that described in Example (1b), 1.37 g of N-[phenyl-(3-nitrophenyl)methyl]-N-[(R)-1-(3-fluorophenyl)ethyl)amine [prepared as described in step (a) above], 2.14 g of nickel chloride hexahydrate and 623 mg of sodium borohydride were reacted, to obtain 1.16 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1C=C2C(=CC=1O)NC(=O)CC2)[CH:2]=C.[CH2:16]([C:19]1[C:20]([OH:30])=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:17]=[CH2:18].C(Br)C=C>CO.[OH-].[K+]>[CH2:16]([C:19]1[C:20]([O:30][CH2:4][CH:1]=[CH2:2])=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:17]=[CH2:18]
Reactant: C=CCc1c(O)ccc2c1NC(=O)CC2
Reactant: C=CCc1cc2c(cc1O)NC(=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: CO
Product: C=CCOc1ccc2c(c1CC=C)NC(=O)CC2
Yield: 60 %

Procedure:
6.1 Grams of the mixture of 6-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 8-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone obtained in Example 8 was dissolved in 200 ml of methanol containing 1.8 g of potassium hydroxide. Under stirring, 3 ml of allyl bromide was added thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and further stirred at 60° C. for 1 hour. After the reaction was finished, the reaction mixture was concentrated under reduced pressure, next 200 ml of water was added and stirred vigorously, then extracted with 500 ml of ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to dryness. This mixture was subjected to purification by means of a flush column chromatography by using methylene chloride-methanol (100:1). The first eluted portion was collected and concentrated under reduced pressure, there was obtained 4.4 g (60%) of 8-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone. Colorless needle-like crystals (recrystallized from ethyl acetate-n-hexane). Melting point: 119°-121° C.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[OH-].[Li+].OO.S(=O)(=O)(O)[O-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)C(C)(C)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: C1CCOC1
Product: CC1(C)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
6 g (R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-one is added to THF (6 ml). Lithium hydroxide (15.6 ml, 3 mol L−1) is added followed by tetra-butylammonium bromide (0.15 g). This mixture is then added to a mixture of hydrogen peroxide (4.54 g) and THF (12 ml) at 0° C. After 2.5 h, sodium bisulfate solution (12 g, 38-40%) is added. THF is removed in vacuo. Toluene (70 ml) is added and the phases separated. The organic phase is washed with water (15 ml). The phases are separated. The organic phase is concentrated in vacuo and then heptane (60 ml) is added and the mixture cooled to 0° C.). The precipitate is collected by filtration and dried in vacuo to give (R)-5-Biphenyl-4-ylmethyl-3,3-dimethylpyrrolidin-2-one 1H NMR (DMSO): 0.96 (3H), 0.97 (3H), 1.52 (1H), 1.78 (1H), 2.61 (1H), 2.93 (1H), 3.75 (1H), 7.32 (3H), 7.45 (2H), 7.58 (2H), 7.63 (2H), 7.70 (1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.CS(Cl)(=O)=O.[F:23][C:24]1[C:29]([F:30])=[C:28]([CH3:31])[CH:27]=[CH:26][C:25]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CC(N(C)C)=O.O>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH3:31])[CH:27]=[CH:26][C:25]=1[O:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=2)[CH2:5]1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Reactant: Cc1ccc(O)c(F)c1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(C)c(F)c3F)C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 0.023 g (0.10 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in 5 mL THF are added 0.017 mL (0.12 mmol) TEA and the mixture is cooled to 0° C. 0.008 mL (0.10 mmol) methanesulfonyl chloride are added dropwise and the mixture is stirred for 2 h at 0° C. Water is added and the aq. phase is extracted with ethyl acetate (2×). The combined organic layers are dried (MgSO4) and concentrated. The residue is taken up in 1.0 mL DMA and is added to a mixture of 0.014 g (0.12 mmol) 2,3-difluoro-4-methylphenol and 0.039 g (0.12 mmol) Cs2CO3 in 1.0 mL DMA. The resulting mixture is stirred for 12 h at 100° C. After cooling the mixture is directly purified by HPLC (MeOH/water (+0.1% NH4OH)) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[C:17]([NH2:23])[CH:16]=1.C(N(CC)CC)C>ClCCl>[NH2:23][C:17]1[CH:16]=[C:15]([Cl:14])[C:20]([Cl:21])=[CH:19][C:18]=1[NH:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)ccc1C(=O)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of 2-methoxy-4-cyanobenzoyl chloride (2 g, 10 mmol) in dichloromethane (20 ml) was added dropwise in 1 h to a solution of 4,5-dichlorophenylendiamine (3.54 g, 20 mmol) and triethylamine (10.1 g=13.9 ml, 100 mmol) in dichloromethane (20 ml). Stirring was continued for additional two hours. The solvent was removed under vacuum and the residue was triturated with water (50 ml), filtered and dried at 50° C. under vacuum. The solid was suspended in diethyl ether (150 ml), stirred for 1 h, filtered and dried under vacuum to give 2.9 g of N-(2-amino-4,5-dichlorophenyl)-2-methoxy-4-cyanobenzamide (yield 43%), mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][CH2:30][CH2:31][CH3:32])[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][CH2:30][CH2:31][CH3:32])[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][NH:17][CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CCCSc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCN(C(=O)OC(C)(C)C)CC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCSc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCNCC21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-6-(propylthio)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.090 g, 0.182 mmol) was dissolved in CH2Cl2 (5 mL). Trifluoracetic acid (0.3 mL, 0.182 mmol) was added and the reaction mixture was stirred at rt under N2 for 2.5 h when all the starting material was consumed. The reaction mixture was cooled to 0° C. and 5M NaOH (10 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography (first eluting with 3:1 Hexane:EtOAc, and then eluting with 2:6:92 conc. NH4OH:CH3OH:CH2Cl2 to elute the product). Example 252 (0.070 g) was obtained in 97% yield. HRMS (FAB) calcd for C20H21CL2NOS +H1 394.0799, found 394.0797.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[Li].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:12]=[N:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:12]([NH:13][C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: [Li]c1nccs1
Reactant: COc1ccc(C=Nc2ccncc2)cc1OC
Product: COc1ccc(C(Nc2ccncc2)c2nccs2)cc1OC

Procedure:
The title compound is prepared in a similar manner to Examples 5, 6 and 7 by reacting 2-thiazolyl lithium (obtained from 2-bromothiazole and butyl lithium) with 4-(3,4-dimethoxybenzylideneamino)pyridine.
Reaction SMILES: Cl(O)(=O)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12]N2CCCC2)[NH:10][CH:11]=1.[OH-].[Na+].S(OC)(OC)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12][C:27]#[N:28])[NH:10][CH:11]=1
Reactant: Clc1c[nH]c(CN2CCCC2)c1
Reactant: [C-]#N
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CS(C)=O
Solvent: COS(=O)(=O)OC
Product: N#CCc1cc(Cl)c[nH]1
Temperature: 25 °C

Procedure:
An aqueous solution of 114.0 g. of the product of Example VI is converted into the free base form by addition of 10% aqueous sodium hydroxide solution. The solid that is thus precipitated is filtered, washed with water and dried to give 67.1 g. (0.364 mole) of free base. The free base is dissolved in 350 ml. of dry dimethyl sulfoxide and stirred in an ice bath while 45.9 g. (0.364 mole) of dimethyl sulfate is added dropwise. The whole is then stirred for a half hour and warmed to room temperature, whereupon 20.0 g. (0.41 mole) of freshly ground and dried sodium cyanide is added all at once. After the resulting solution has been stirred for 2 hours at ambient temperature, it is poured onto ice and this aqueous solution is extracted four times with 250 ml. of diethyl ether. The combined ether extracts are washed successively with brine, 3N hydrochloric acid solution, aqueous sodium bicarbonate solution, and brine, and are dried over sodium sulfate. Evaporation of the ether yields 4-chloropyrrole-2 -acetonitrile as a brown oil.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C(OO)=[O:24])C=CC=1>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH:1]2[CH2:5][CH:4]3[CH:3]([O:24]3)[CH2:2]2)=[CH:13][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COC2CC=CC2)cc1
Solvent: ClCCl
Product: COc1ccc(COC2CC3OC3C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-[(cyclopent-3-en-1-yloxy)methyl]-4-methoxybenzene (9.64 g, 47.2 mmol) in dry DCM (52 ml) at 0° C. under an atmosphere of nitrogen was added 3-chlorobenzene-1-carboperoxoic acid (CAS number 937-14-4; 16.29 g, 94 mmol). The reaction mixture was warmed to room temperature for 17 hours then filtered. The filtrate was washed with a saturated solution of sodium thiosulfate and then with a saturated solution of sodium bicarbonate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH2:3]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([Br:1])[C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCCC1Cc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step AAD (1): Followed the method of B. Miller and H.-S. Wong Tetrahedron 1972, 28, 2369. Bromine (0.082 mL, 1.59 mmol) in was added dropwise over a period of 15 min to a solution of 2-benzylcyclohexanone (300 mg, 1.593 mmol) in chloroform (5 mL). The reaction mixture was stirred at rt for 2 h, then concentrated in vacuo to afford 2-benzyl-6-bromocyclohexanone. The crude product, which is prone to decomposition, was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCC1=C(C)[C@@H](O[Si](C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
1 To a solution of (S)-4-hydroxy-3-methyl-2(2-propynyl)-cyclopent-2-ene-1-one (12.88 g) and triethylamine (13.2 g) in tetrahydrofuran (200ml) was added dropwise chlorotrimethylsilane (10.4 g) for 5 minutes under ice-water cooling, then the solution was stirred for 2 hours under ice-water cooling, and 13 hours at room temperature. Then this solution was poured into ice-water and extracted twice with diethyl ether. The ether layers were combined and washed twice with brine. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resultant residue was subjected to column chromatography over florisil (eluent; n-hexane:ethyl acetate=20:1) to afford (S)-4-trimethylsilyloxy-3-methyl-2-(2-propynyl )-cyclopent-2-ene-1-one (18.0 g, yield 79.1% ) as a pale yellow oil.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[C:24](O)=[O:25]>>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NCC(F)F
Product: Cc1ccccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-(4-o-tolyl-pyridin-3-yl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (34%). MS (ESI): m/z=490.11 [M+H]+.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([C:30]1[S:34][C:33]2=[CH:35][N:36]=[CH:37][N:32]2[CH:31]=1)(=[O:29])[NH2:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:33]4[S:34][C:30]([C:27](=[O:29])[NH2:28])=[CH:31][N+:32]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: NC(=O)c1cn2cncc2s1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4sc(C(N)=O)c[n+]4c3)[C@H](C)[C@H]12
Yield: 6.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 107 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 74 mg of 2-carbamoylimidazo[5,1-b]thiazole were used, thereby obtaining 7.4 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.C(Cl)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[O:14][C:12](=[O:13])[CH2:11]2
Reactant: O=C(O)Cc1cc(Br)ccc1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2cc(Br)ccc2C(=O)O1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
A mixture of 4-bromo-2-(carboxymethyl)benzoic acid (1.00 g, 3.86 mmol) in acetyl chloride (13.72 ml, 193 mmol, 50.0 equiv.) was stirred at 150° C. for 15 min. in a microwave. Upon completion of the reaction, the excess solvent was concentrated and dried to yield 740 mg of 6-bromoisochroman-1,3-dione as a white solid which was used as such without any further purification.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][NH:8][C:6]=2[N:7]=1.Cl.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:28][C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cn1c(Cl)nc2[nH]nc(Nc3ccccc3)c2c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(N[C@@H]2CCCC[C@H]2O)nc2[nH]nc(Nc3ccccc3)c2c1=O
Yield: 64.7 %

Procedure:
A solution of 6-chloro-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (75.8 mg, 0.275 mmol), trans-2-amino-cyclohexanol hydrochloride (83.4 mg, 0.55 mmol) and DIPEA (144 μL, 0.825 mmol) in DMF (3 mL) is heated at 110° C. overnight. The reaction mixture is evaporated to remove DMF under reduced pressure. The residue is then purified by chromatography to give 63.1 mg product (Yield: 64.7%). MS (ESI) m/z 355.0 [M+H]+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:13][C:14]([F:27])([F:26])[C:15](=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.O>C(O)(=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH2:16][C:15]([C:14]([F:13])([F:26])[F:27])=[N:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C2CC(C(F)(F)F)=NN2c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 45 %

Procedure:
A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.82 g, 3.69 mmoles) and (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.79 g, 3.69 mmoles) in 15 ml of acetic acid is refluxed for 3 hours under a nitrogen atmosphere. It is cooled, poured over water and extracted with AcOEt. The organic solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under vacuum. The crude product thus obtained is crystallised from EtOH-petrol ether to give 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (0.65 g, yield: 45%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][C:12](=O)[CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[K+]>C(O)COCCO>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CC(=O)CC(c2ncccc2C)N1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Temperature: 125 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 3,3″-dimethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,2′;6′,2″]terpyridin-4′-one (9.6 g, 34.1 mmol) in diethylene glycol (170 mL) was added hydrazine monohydrate (90 mL, 2.89 mol) and potassium hydroxide pellets (57.4 g, 1.02 mol) and the reaction stirred at 125° C. for 2 hours. 50 mL of hydrazine distilled off and water (200 mL) was added the remaining mixture. The solution was extracted with CH2Cl2 (4×300 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL) and washed with a saturated solution of NaHCO3 (3×100 mL) to remove the residual diethylene glycol. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 8.82 g (97%) of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine as yellow solid. 1H NMR (CDCl3) δ 1.50-1.65 (m, 2H), 1.75-1.95 (m, 3H), 2.13 (m, 1H), 2.37 (s, 6H), 3.09 (br t, 1H), 4.15-4.25 (m, 2H), 7.02 (dd, 2H, J=7.5, 4.8 Hz) 7.38 (d, 2H, J=7.5 Hz), 8.46 (br d, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.C([O-])([O-])=O.[Na+].[Na+].[O:41]1[C:45](B(O)O)=[CH:44][C:43]2[CH:49]=[CH:50][CH:51]=[CH:52][C:42]1=2>COCCOC.O>[O:41]1[C:42]2=[CH:52][CH:51]=[CH:50][C:49]2=[CH:43][CH:44]=[C:45]1[N:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:12]([CH:11]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)=[O:21]
Reactant: CC(C)(C)c1ccc(C(Nc2ccc(C(=O)O)cc2)C(=O)Nc2ccc(I)cc2)cc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1ccc(C(Nc2ccc(C(=O)O)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-amino}-benzoic acid acid (340 mg, 0.6 mmol) was taken up in 8 mL of DME, 4 mL of ethanol and 2 mL of water. Na2CO3 (254 mg, 2.4 mmol), PdCl2(O-tolyl)2 (61 mg, 0.0078 mmol) and benzo[B]furan-2-boronic acid (194 mg, 1.2 mmol) were then added, flushed with nitrogen and heated to reflux for 1 h. Cooled to RT, EtOAc (20 mL) was added and extracted with water (20 mL). The organic layer was washed again with water (20 mL), dried over sodium sulfate, filtered and the organic layer was removed under reduced pressure to give a white solid (120 mg, 100%). 1H NMR showed the compound to be very clean and sufficient for the following step.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:15]([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[F:1])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: O=C(O)CCC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1cc(C(=O)CCC(=O)O)ccc1F

Procedure:
A stirred mixture of 3-(4-fluoro-3-nitrobenzoyl)propionic acid, cyclohexene, palladium on charcoal, and ethanol, was heated under reflux for 18 hours. Evaporation of the filtered solution gave 3-(3-amino-4-fluorobenzoyl)propionic acid.