Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)nc1
Product: Cc1ccc(CCl)nc1
Yield: 73 %

Procedure:
Thionyl chloride (30 ml) was added to (5-methylpyridin-2-yl)methanol (3.0 g, 24.3 mmol) at 20° C. under nitrogen. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC). The reaction mixture was concentrated under reduced pressure upon which it was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 6% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 2-(chloromethyl)-5-methylpyridine (2.5 g, 73%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 4.6 (s, 2H), 2.3 (s, 3H). MS: [M+H]+: m/z=142.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:13][C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1ccc(C=O)c(O)c1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Temperature: 0 °C

Procedure:
To a solution of 3,4-dimethoxy-2-hydroxybenzaldehyde (0.5 g) in acetic acid (10 ml) was added fuming nitric acid (0.12 ml). The reaction mixture was poured into ice water, the product extracted into ethyl acetate, washed with water, dried and evaporated. The product was triturated with water and filtered. Yield: 0.15 g.
Reaction SMILES: CN(C)C=O.[O-]CCCC.[K+].[CH3:12][C:13](=[CH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[C:20]1([CH3:26])[CH3:25])[C:14](=[O:16])[CH3:15]>C(O)(=O)C>[CH3:12][CH:13]([CH:17]=[CH:18][CH:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[C:20]1([CH3:25])[CH3:26])[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)C(C)=CCC1CCC(C)C1(C)C
Agent: CCCC[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)C(C)C=CC1CCC(C)C1(C)C
Temperature: 10 °C
Yield: 20.8 %

Procedure:
To a mixture of 100 ml of N,N-dimethylformamide and 13 g (0.18 mole) of powdered potassium butoxide, maintained at 20°-30° C. are added slowly within 1 hour 25 g (0.12 mole) of 3-methyl-5-(2,2,3-trimethyl-cyclopent-1-yl)-pent-3-ene-2-one. The resultant mixture is stirred at ambient temperature for 4 hours (reaction is monitored by GC) and is cooled to 10° C. The reaction mixture is drained out of the reaction flask into a beaker containing 20 ml of glacial acetic acid and 50 ml of ice water which are being stirred by means of a magnetic stirrer. The mixture is stirred for 5-10 minutes and is then transferred to a separatory funnel. This mixture is extracted with three 50 ml portions of toluene. The toluene extracts are combined and washed with three 50 ml portions of 10% sodium bicarbonate solution and one 100 ml portion of saturated sodium chloride solution. The solvent is removed by rotary evaporation and the oil is fractionally distilled to yield 5.2 g of 3-methyl-5-(2,2,3-trimethyl-cyclopent-1-yl)-pent-4-en-2-one (mixtures of isomers).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]>S(=O)(=O)(O)O.C(O)(=O)C.ClCCl>[Cl:9][C:10]1[CH:15]=[C:14]([I:1])[C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cl)c(-c2ccccc2F)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2ccccc2F)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
N-Iodosuccinimide (683 mg, 3.04 mmol) was added to a solution of 2-chloro-2′-fluoro-5-methoxybiphenyl (Preparation 96, 749 mg, 3.16 mmol) in concentrated sulfuric acid (0.09 mL), acetic acid (4.7 mL) and dichloromethane (4.7 mL). The resulting mixture was stirred at room temperature for 18 hours and then partitioned between dichloromethane (30 mL) and water (5 mL). The organic phase was separated and washed with water (2×5 mL), brine (5 mL), dried over MgSO4, filtered and evaporated to give a red oil. Column chromatography purification on silica, eluting with dichloromethane:heptanes (1:9) gave the title compound (671 mg, 58%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH:9](O)[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[H-].[Na+].C[OH:24]>CN(C=O)C>[CH3:1][N:2]([CH2:9][CH2:10][O:24][C:19]1[CH:20]=[CH:13][CH:14]=[CH:15][C:16]=1[CH:17]=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(O)N(C)c1ccccn1
Reactant: O=Cc1ccc(F)cc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccccc1C=O)c1ccccn1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
2-(N-methyl-N-(2-pyridyl)amino ethanol (50 gms, 0.32M) and 4-fluoro benzaldehyde (68 gms, 0.547M) were dissolved in DMF (500 ml) and sodium hydride (2 gms) was added. The reaction mass was stirred for 15 minutes and the temperature was maintained below 35° C. Sodium hydride (4 gms) was added again and the reaction mass stirred for 15 minutes. Subsequently 8 and 10 gms of sodium hydride were sequentially added at 15 minute intervals. The reaction was monitored by HPLC. After completion of reaction, the reaction mass was cooled to 5° C., and methanol (30 ml) was added slowly. The reaction mass was then quenched into water (approx 21 trs) and extracted with ethyl acetate (4×500 ml). The combined organic layers were washed with water (6×500 ml). The organic layer was dried over sodium sulphate and concentrated to obtain the title compound as an oil (105 gms, 84% HPLC purity).
Reaction SMILES: [OH:1][CH2:2][C:3]1([OH:27])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH2:4]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:28][S:29]([O:1][CH2:2][C:3]1([OH:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(COS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-hydroxymethyl-4-hydroxy-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.00 mmol) with methanesulfonyl chloride (1.20 mmol) and triethylamine (1.50 mmol) in dichloromethane (15 ml) at a temperature 0-10° C. for 4 hours and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13]>ClC(Cl)C>[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([C:25]=1[C:5](=[O:7])[CH3:6])=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:5](=[O:7])[CH3:6])=[CH:21][CH:20]=2)=[O:16])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1C(C)=O
Product: CCOC(=O)c1cc2cc(C(C)=O)ccc2[nH]1
Temperature: 40 °C
Reaction time: 10 h
Yield: 13 %
Yield: 52 %

Procedure:
Aluminum chloride (7.75 g, 0.058 mol) was suspended in 200 ml of anhydrous dichloroethane at room temp. followed by a slow addition of acetic anhydride (2.74 mL, 0.03 mol). The mixture was stirred at room temp for 10 minutes after which, 1H-indole-2-carboxylic acid ethyl ester (1b, 5.0 g, 0.0264 mol) was added as a solution in 15 mL of dichloroethane. The reaction mixture was stirred under nitrogen at 40° C. for 10 h. The reaction was quenched with an ice-water mixture and the organic layer was washed with water (3×). The organic phase was dried over anh. Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 (4% Ethyl acetate/96% CH2Cl2) provided 3.2 g of 3-acetyl-1H-indole-2-carboxylic acid ethyl ester 2b (52%) and 770 mg of 5-acetyl-1H-indole-2-carboxylic acid ethyl ester 3b (13%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([F:67])=[C:49]([C:51]23[CH2:58][CH:57]2[CH2:56][CH2:55][S:54][C:53]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[N:52]3)[CH:50]=1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([F:67])=[C:49]([C:51]34[CH2:58][CH:57]3[CH2:56][CH2:55][S:54][C:53]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[N:52]4)[CH:50]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(N)ccc3F)CC2CCS1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2CCS1
Temperature: 23 °C
Reaction time: 20 h
Yield: 39.4 %

Procedure:
Commercially available 5-chloro-2-pyridinecarboxylic acid (30 mg, 0.19 mmol) was dissolved in dichloromethane (3 ml) and DMF (1 ml), then diisopropylethylamine (85 μl, 0.50 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (87 mg, 0.23 mmol) were added at 23° C. After 15 min of stiffing tert-butyl (1SR,7SR)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A8a) (53 mg, 0.15 mmol) was added. The brown solution was stirred for 20 hours at 23° C. The grey reaction mixture was poured on ice cold sat. NaHCO3 solution and extracted twice with dichloromethane. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a brown oil which was chromatographed on 5 g silica gel with cyclohexane/ethyl acetate 1:1 to give the tert-butyl (1SR,7SR)-1-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (29 mg; 31%) as a light yellow oil. MS (ISP): m/z=491.1 [(M+H)+] and 493.2 [(M+2+H)+].
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]>O1CCCC1.O.Cl>[CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(OCc3ccccc3C(=O)O)cc2)cc1
Yield: 7.7 %

Procedure:
Methyl 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (0.18 g, 0.38 mmol) was dissolved in a mixture of tetrahydrofuran and water 7:1 (5 ml). The reaction was performed in a single node microwave oven (150° C. in 7 minutes). The mixture was diluted with HCl (2 ml, 1 M) and the organic phase was isolated. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 13 mg of 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]-methyl}benzoic acid (yield 7.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH2:26])[C:17]2=[O:27])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N:26]([S:36]([CH3:35])(=[O:38])=[O:37])[S:36]([CH3:35])(=[O:38])=[O:37])[C:17]2=[O:27])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)cc1OC
Temperature: 5 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of 2-[1-(3,4-dimethoxyphenyl)-3-oxobutyl]-4-aminoisoindoline-1,3-dione (1.02 g, 2.77 mmol) and triethylamine (1.40 g, 13.85 mmol) in methylene chloride (40 mL) was cooled to 5° C. Methanesulfonyl chloride (1.27 g, 11.08 mmol) was added at 5-8° C. and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with sat. Sodium bicarbonate (20 mL), 1N hydrogen chloride (20 mL), water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give 2-[1-(3,4-dimethoxyphenyl)-3-oxobutyl]-4-[bis(methylsulfonyl)amino]isoindoline-1,3-dione (1.18 g, 81%) as a white solid: mp 194-196° C.; 1H NMR (DMSO-d6) δ 8.02-7.93 (m, 3H), 6.99-6.90 (m, 3H), 5.65 (t, J=6.7 Hz, 1H), 3.75-3.65 (m, 1H), 3.71 (s, 6H), 3.56 (s, 6H), 3.53-3.46 (m, 1H), 2.11 (s, 3H); 13C NMR (DMSO-d6) δ 205.79, 166.58, 165.78, 148.64, 148.32, 138.48, 135.86, 132.68, 131.50, 129.85, 129.15, 125.06, 119.35, 111.58, 110.91, 55.49, 55.39, 49.27, 44.52, 43.53, 43.49, 29.92; Anal. Calcd. for C22H24N2O9S2: C, 50.37; H, 4.61; N, 5.34, S, 12.23. Found: C, 50.43, H, 4.77; N, 5.16; S, 12.22.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[N:8]=1.[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH3:9][C:7]1([CH3:10])[NH:8][C:3](=[NH:12])[CH2:4][CH2:5][CH2:6]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(C)(C)CCC1
Solvent: CO
Product: CC1(C)CCCC(=N)N1
Product: Cl

Procedure:
The product of EXAMPLE 159 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH2:16][C:15](=O)[NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>CC1C=CC(C)=CC=1>[Cl:20][C:15]1[NH:14][C:11]2=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]2[CH:16]=1
Reactant: O=C1Cc2cc(-c3cccc(F)c3)cnc2N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(C)cc1
Product: Fc1cccc(-c2cnc3[nH]c(Cl)cc3c2)c1
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A suspension of 5 (16.52 g, 72.4 mmol) in neat P(O)Cl3 (21.5 mL, 0.231 mol) was stirred at 100-105° C. for 4 h. The mixture was then cooled to rt., diluted with p-xylene (100 mL) and concentrated to dryness in vacuum. The residue was separated between saturated aqueous NaHCO3— AcOEt. 10% aqueous solution of Na2CO3 was added to basify the aqueous layer to pH 9. Organic phase was separated and the aqueous layer was extracted with AcOEt (8×300 mL). Combined organic solutions were dried MgSO4, concentrated, and the residue was purified by silicagel chromatography (SGC) using CH2Cl2:AcOEt as eluent in gradient to afford recovered starting material 5 (0.76 g, 5%). The desired product was then crystallized from acetone to afford 6 (10.06 g, 56%), thin tan needles. 1H NMR (400 M CDCl3) δ 6.47 (s, 1H), 7.08 (tdd, J=8.1, 2.3, 1.5 Hz, 1H), 7.33 (ddd, J=9.9, 2.3, 1.6 Hz, 1H), 7.38-7.48 (m, 2H), 8.03 (d, J=2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 11.46 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])/[C:17](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:15]3=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])[CH:17]([CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][C:15]3=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 51.7 %

Procedure:
To a solution of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (9 mg, 0.02 mmol) in methanol (0.1 ml) was added 5% palladium on activated charcoal (1 mg) and the reaction stirred for 6 hours under 1.5 bar of hydrogen. The solution was then filtered through a pad of Celite, washed with methanol (10 ml) and concentrated in vacuo to give a white solid, which was purified by reverse phase preparative HPLC (eluting with acetonitrile/water) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl ]-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])/[CH:35]=[CH:34]/[C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccncc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(/C=C/c1ccncc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
To a solution of the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (41 mg, 0.10 mmol) obtained in Example 351, (E)-3-(pyridin-4-yl)acrylic acid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol), and N-methylmorpholine (0.011 ml, 0.10 mmol) in dichloromethane (1 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.10 mmol) at 0° C. The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer thus obtained was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with ethyl acetate was concentrated under reduced pressure. The solid thus obtained was washed with diethyl ether and then collected by filtration, whereby the title compound (35 mg, 0.065 mmol, 65%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH3:14][NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>>[ClH:1].[CH3:14][N:15]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1)[C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN[C@@H]1CCCC[C@H]1C1NCCc2ccccc21
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Product: CN(C(=O)COc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@H]1C1NCCc2ccccc21
Product: Cl

Procedure:
The title compound was prepared according to the method described in Example 2, using 3,4-dichlorophenoxyacetic acid (2.14 g, 9.7 mmol) and (±)-trans-N-methyl-N-[2-(1,2,3,4-tetrahydroisoquinolinyl)cyclohexyl]amine prepared in Example 17 (2.25 g, 9.2 mmol). The crude product was recrystallised from hot methanol, to give the title compound which was slightly hygroscopic. Yield 3.19 g (72%). Carbon-13 NMR data in accord.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[O:13][CH2:12]1.[OH-].[K+]>CO>[O:13]1[C:14]2([CH2:19][CH2:18][C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)=[CH:16][CH2:15]2)[O:21][CH2:11][CH2:12]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 87.3 %

Procedure:
5-Fluoroindole (4.96 g, 0.036 mol), 1,4-cyclohexanedione monoethylene ketal (7.17 g, 0.046 mol) and potassium hydroxide (6 g, 91 mmol) were heated to reflux in 70 ml methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 8.59 g (86%) of product as a white solid: mp 153-155° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1B(O)O)=O)(C)(C)C.O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.COCCOC>[NH3:1].[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:38]2[NH:37][C:45]3[C:40]([CH:39]=2)=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: N
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of benzyl {[trans-4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.00 g, 0.00180 mol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (0.517 g, 0.00198 mol), 1,2-dimethoxyethane (7.7 mL), water (1.4 mL, 0.081 mol) and Cesium Carbonate (1.17 g, 0.00360 mol) degassed three times, treated with tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.0002 mol) and degassed once more. The resulting mixture was heated at 100° C. overnight before being diluted with EtOAc (40 mL), washed with water (2×30 mL) and brine (20 mL) then dried over Na2SO4 and concentrated in vacuo. The crude product thus isolated was chromatographed over silica gel eluting with hexane→EtOAc:hexane: 5% 2M NH3 in MeOH 1:1:0.05 to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 1.13-1.22 (m, 2H), 1.75-1.86 (m, 2H), 1.94-1.97 (m, 2H), 2.11-2.13 (m, 2H), 2.86 (m, 1H), 3.12-3.16 (m, 2H), 4.82 (m, 1H), 5.12 (s, 2H), 5.69 (br, 2H), 6.78 (s, 1H), 7.13-7.15 (m, 2H), 7.19-7.25 (m, 2H), 7.32-7.38 (m, 5H), 7.42 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 9.09 (br, 1H). MS (ES+): m/z 495 [MH+].