Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27](O)[CH2:26]1)(=[O:24])=[O:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:27]2[CH2:28][CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(S(C)(=O)=O)C2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-piperidin-3-ol.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[C:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:6]=1)[CH2:2][CH3:3].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:55]([N:62]1[CH2:66][CH2:65][CH:64]([NH2:67])[CH2:63]1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O.O>[CH2:55]([N:62]1[CH2:66][CH2:65][CH:64]([NH:67][C:11]([C:10]2[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:8][CH:9]=2)=[O:13])[CH2:63]1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NC1CCN(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid (A3, 90 mg) in N,N-dimethylformamide (2 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg) and 1-hydroxybenzotriazole monohydrate (45 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (153 μL) and 1-benzyl-3-aminopyrrolidine (53 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure. The obtained solid matter was purified by basic silica gel column chromatography to obtain N-(1-benzylpyrrolidin-3-yl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (E9, 117 mg).
Reaction SMILES: [Br-].[CH:2]12[C:14](=[N+]3CCCC3)[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:3]2.Cl.[OH2:21]>>[CH:2]12[C:14](=[O:21])[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:3]2
Reactant: c1ccc2c(c1)CC1CCC(C2)C1=[N+]1CCCC1
Reactant: O
Agent: Cl
Agent: [Br-]
Product: O=C1C2CCC1Cc1ccccc1C2

Procedure:
1-Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylidene-pyrrolidinium bromide (225 mg, 0.70 mmol) was dissolved in water (5 mL) and 2 M aqueous HCl (5 mL) was added. The mixture was heated at reflux for 16 h, cooled and extracted into DCM. The organic extracts were concentrated to give tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one (130 mg) as a white crystalline solid. 1H NMR (CDCl3, 360 MHz) δ 7.19 (4 H, s, aromatic), 2.99-2.86 (4 H, m, benzylic), 2.61-2.57 (2 H, m, bridgehead H), 1.90-1.80 (2 H, m), 1.33-1.26 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]3[CH3:20])[N:11]=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH3:26])[N:9]=2)=[CH:4][CH:3]=1.Br[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([Br:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.O>[Br:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([N:17]2[CH2:18][CH2:19][N:14]([C:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])[N:11]=3)[C@H:15]([CH3:20])[CH2:16]2)=[N:29][CH:30]=1
Reactant: C[C@@H]1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1
Reactant: Cc1cc(Br)cnc1Br
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1

Procedure:
Heat a mixture of 4-(4-fluoro-phenyl)-6-(2-(R)-methyl-piperazin-1-yl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine (400 mg, 1.13 mmol), 2,5-dibromo-3-methyl-pyridine (367 mg, 1.46 mmol), and DIEA (218 mg, 1.69 mmol) in DMA at 135° C. for 96 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc-Hexanes (1:10) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]4([CH3:25])[OH:24])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1>C1COCC1.C[O-].[Na+].C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]4([CH3:25])[OH:24])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(O)CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)ncc1F
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(O)CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-((2-(5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol, 28b, in THF was added a few drops of 25% sodium methoxide at room temperature. The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was diluted with ethyl acetate and brine. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by preparatory HPLC to afford two diastereomers.
Reaction SMILES: [CH2:1]1[S:5][C@H:4]([CH2:6][OH:7])[O:3][C@@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1.Cl>CO.O1CCOCC1>[NH2:15][C:11]1[C:10]([F:16])=[CH:9][N:8]([CH:2]2[O:3][CH:4]([CH2:6][OH:7])[S:5][CH2:1]2)[C:13](=[O:14])[N:12]=1
Reactant: Nc1nc(=O)n([C@@H]2CS[C@H](CO)O2)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(=O)n(C2CSC(CO)O2)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of (−)-FTC [32 (2R, β/α)] (60:40 of a β:α anomer mixture, 3.0 g) was dissolved in methanol (30 ml), cooled to 0° C., and treated with a 4.0 M solution of HCl in 1,4-dioxane (3.3 ml [1.1×]). The solution was stirred for 20 minutes, and subsequently concentrated to dryness affording an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:15](=O)([O:22]C1C=CC([N+]([O-])=O)=CC=1)[O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:22])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Brc1ccc(N2CCCNCC2)nc1
Product: CNC(=O)COC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Yield: 70.6 %

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 0.95 g (3.70 mmol) of 1-(5-bromo-2-pyridyl)-1,4-diazepane, obtained in step 11.2., and 0.94 g (3.70 mmol) of 2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate, prepared in step 2.2. of Example 2, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane and then with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.97 g of product is obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].Br.[OH-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12]
Reactant: COc1cccc(CC2CCCN2C)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCCC1Cc1cccc(O)c1

Procedure:
Boil 10.5 g of 2-(3-methoxybenzyl)-1-methylpyrrolidine under reflux for 50 hours in a mixture of 60 ml of acetic acid and 60 ml of 48% strength hydrobromic acid. Pour the resulting reaction mixture onto ice, adjust its pH to 10 with 6 N sodium hydroxide solution and extract it 3 times with diethyl ether. Combine and dry the ether phase, distil off the solvent and distil the residue under a vacuum to obtain 7.95 g (79% of theory) of the title compound (b.p. 128° to 130° at 0.006 mm of Hg). The fumarate (from isopropanol) melts at 189° to 191°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11](F)[N:12](F)F)=[O:10])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:22]CC(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([Cl:22])[C:9]([NH:11][NH2:12])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(Cc1cccc(Cl)n1)N(F)N(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: NNC(=O)C(Cl)c1cccc(Cl)n1
Reaction time: 1 h

Procedure:
A mixture of 3.0 g. of 2-chloro-6-hydrazinopyridine (prepared in Example 1), 1.7 g. of pyridine and 35 ml. of methylene chloride is treated with 2.5 g. of chloroacetyl chloride according to the procedure of Example 2. The reaction mixture is stirred for one hour, then is filtered and washed with methylene chloride to collect 2.3 g. of colorless solid. The solid is recrystallized from tetrahydrofuran-hexane to give the product of the Example m.p. 176°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][C:8]1=[O:12])(=[O:15])[CH3:14]
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)N(C(C)=O)C(=O)C2

Procedure:
Prepared from 6-methoxy-2-indolinone (prepared according to Quallich, G. J.; Morrissey, P. M.; Synthesis 1993, 51) and acetic anhydride
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[CH3:22][S:19]([NH:18][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[CH:15][C:16]([NH:17][C:3](=[O:4])[CH2:2][Cl:1])=[C:7]2[OH:6])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Nc1cccc2c(O)c(N)ccc12
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc2c(O)c(NC(=O)CCl)ccc12
Temperature: 85 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
0.32 ml of chloroacetyl chloride (4 mmol) was introduced into a suspension of 1 g of N-(5-hydroxy-6-aminonaphthalen-1-yl)methanesulphonamide (4 mmol, prepared according to the method described in Patent U.S. Pat. No. 4,956,456) and 0.4 g of calcium carbonate (4 mmol) in 50 ml of dioxane, with stirring and under an inert atmosphere. The reaction medium was stirred for 2 hours at 85° C. and then cooled to 30° C. The suspension was filtered on sintered glass and the inorganic salts were rinsed twice with a minimum of dioxane. The combined organic phases were poured over 100 ml of ice-cold water. The precipitate formed was drained, washed twice with water and dried under vacuum to constant weight to give 1.12 g of N-(5-methanesulphonylamino-1-hydroxynaphthalen-2-yl)-2-chloroacetamide in the form of a pink powder, with a yield of 84%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].[BH4-].[Na+]>N1C=CC=CC=1>[F:20][C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:23](=[O:25])(=[O:24])[N:22]2[CH3:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(F)c2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2cccc(F)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 38.3 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-fluoro-phenyl)-methanone (Intermediate 374) (100 mg, 0.38 mmol), N-methylsulfamoyl chloride (Intermediate 213) (146 mg, 1.13 mmol) and NaBH4 (14 mg, 0.38 mmol) in pyridine (3 ml) gave the title compound (50 mg, 39%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38]2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:49][C:46]3[CH:47]=[CH:48][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH2:38][CH2:39]4)=[CH:44][CH:45]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)nn12
Yield: 76.2 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.239 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 164.97 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a lyophilized powder. (M+H)=498.9. 1H NMR (400 MHz, DMSO, d6) δ 9.42 (s, 1H), 8.94 (s, 1H), 7.80 (dd, 1H, J=1.60, 6.00 Hz), 7.69 (d, 2H, J=8.93 Hz), 7.46 (m, 1H), 7.20 (d, 1H, J=8.28 Hz), 7.13 (m, 3H), 6.94 (m, 2H), 3.70 (s, 3H), 3.67 (m, 7H), 3.01 (m, 6H), 2.83 (s, 3H), 2.07 (m, 2H), 1.79 (m, 2H).
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>C(O)(C)(C)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][C:11]([C:12]#[N:13])([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17]
Reactant: C=CC(=O)OC
Reactant: N#CCc1cccc2ccccc12
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1cccc2ccccc12
Yield: 59 %

Procedure:
A mixture of 20.9 g. (0.125 mole) of the known compound (1-naphthyl)acetonitrile and 58 ml. of methyl acrylate in 60 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 19 ml. of 40% methanolic Triton B in 28 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at refux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.5 mm. to give 24.96 g. (59% yield) of dimethyl-4-cyano-4-(1-naphthyl)pimelate, having a boiling point of 209° to 219°C. The NMR spectrum of the compound confirms its expected structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:17])[C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH-].[Na+].C(OCC)(=O)C.CCCCCC.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:17])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COC(=O)C(C)c1ccc(S(C)(=O)=O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(F)c1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of methyl 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoate (2.1 g, 0.008 mol) in methanol (21 mL, 10 times), a solution of sodium hydroxide (0.32 g, 1 eq) in water (3 mL) was added at 0° C. The contents were allowed to come to room temperature and the mixture was stirred for 2 h. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, methanol was distilled off completely and the residue obtained was taken in water. The contents were acidified to a pH of 4 with diluted HCl, the precipitate was filtered and dried to yield 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid as a white colored solid (1.7 g, 85%).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([N-]CC(C)C)C(C)C.[Li+].Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:31]([O:33][CH3:34])=[O:32])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: C#Cc1ccc(-c2ccc(CCCCC)cc2)cc1
Agent: CC(C)C[N-]CC(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(-c2ccc(CCC(=O)OC)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-Pentylphenyl)phenylacetylene (2.09 g) in tetrahydrofuran (30 ml) was added dropwise a solution of lithium diisobutylamide in a mixture of tetrahydrofuran and n-hexane (1.60 M, 5.6 ml) at −75° C., and the resultant mixture was stirred for an hour at −78° C. To the mixture was added methyl chloroformate (0.72 ml), and the reaction mixture was allowed to warm to ambient temperature. The solution was diluted with ethyl acetate, and washed in turn with water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude product, which was subjected to column chromatography on silica gel (150 ml), and eluted with a mixture of (n-hexane:ethyl acetate=100:0-9:1, V/V) to give Methyl 3-[4-(4-pentylphenyl)phenyl]propionate (2.20 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][C:10]([CH3:15])=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5])[CH3:2].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[C:13]2[C:8](=[N:9][C:10]([CH3:15])=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(C)nc2c1-c1cccnc1OC
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2cccnc2OC)c2nc(C)ccc2n1Cc1ccccc1F
Temperature: 25 °C
Yield: 96.9 %

Procedure:
3-(2-Methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester B3 (0.2 g, 0.64 mmol) was diluted with DMF (4 mL). To the resulting solution was added 2-fluorobenzyl chloride (0.14 g, 0.96 mmol) and cesium carbonate (0.312 g, 0.96 mmol) and the resulting suspension was allowed to stir at room temperature. After 24 hours the reaction mixture was then diluted with ethyl acetate (50 mL) and water (20 mL) and the layers were separated. The organic layer was sequentially washed with aqueous saturated sodium bicarbonate solution (10 mL), water (10 mL) and saturated brine (10 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue obtained was purified using flash chromatography to provide 1-(2-Fluoro-benzyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester B4 (0.26 g) MS: 420.20 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22]C)[C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1)[CH3:2].Br.[OH-].[Na+]>C(O)(=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC2(CC1)c1ccccc1Sc1c(OC)cccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCN1CCC2(CC1)c1ccccc1Sc1c(O)cccc12
Reaction time: 5 h

Procedure:
A solution of 1'-ethyl-4-methoxythioxanthene-9-spiro-4'-piperidine (1.625 g.) in glacial acetic acid (20 ml.) is added to 48% w/v hydrobromic acid (20 ml.) and refluxed with stirring for 5 hours. The mixture is cooled, diluted with water (500 ml.), cooled in ice and basified with 19N-sodium hydroxide solution and the solution washed with ether (× 3). The aqueous alkaline layer is acidfied to pH 1 with concentrated hydrochloric acid, neutralised with solid sodium bicarbonate and extracted with ethyl acetate (× 3). The combined ethyl acetate extracts are washed with water (× 3), dried over MgSO4 and the ethyl acetate removed by distillation in vacuo. The resulting sticky solid is triturated with ether to give 1'-ethyl-4-hydroxythioxanthene-9-spiro-4'-piperidine, m.p. 223°-225° C. on recrystallisation from dimethyl formamide/methanol/water.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)=[O:4].[BH4-].[Na+]>C(O)C.O.ClCCl>[Cl:1][CH2:2][CH:3]([CH:5]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)[OH:4]
Reactant: O=C(CCl)C1C=Cc2cc(F)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: OC(CCl)C1C=Cc2cc(F)ccc2O1
Reaction time: 2 h
Yield: 70 %

Procedure:
A stirred solution of 2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanone (0.33 g, 1.28 mmol, 88.4% A) in ethanol (2.5 ml) was cooled to 0° C. under nitrogen. NaBH4 (60.1 mg, 1.59 mmol) was added to the solution and the reaction mixture stirred for 2 hours. After checking by GPC that the starting product had disappeared, the mixture was diluted with demineralized water (7 ml) and dichloromethane (7 ml) and the phases separated. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to give crude 2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanol as a mixture of diastereoisomers 54:46 (0.30 g, 70% yield, 67.9% A).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]2=[CH:15][N:14]=1.C(N=C=NCCCN(C)C)C.O[N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=CC=2N=N1.C(N(CC)CC)C.C1(NC)CC1>CN(C=O)C>[CH:42]1([CH2:41][NH:37][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[N:17]([C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][CH:15]=3)[CH:18]=2)=[O:23])[CH2:44][CH2:43]1
Reactant: On1nnc2ccccc21
Reactant: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)O)cn12
Agent: CCN=C=NCCCN(C)C
Agent: CNC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)NCC3CC3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A solution containing 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid (58 mg, 0.18 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (52 mg, 0.27 mmol), 1-hydroxybenzotriazole (24 mg, 0.18 mmol), triethylamine (60 μL, 0.45 mmol) and cyclopropyl methylamine (20 mg, 0.27 mmol) in DMF (1 mL) was stirred at room temperature overnight. Purification by preparative HPLC on reversed phase (0.1% aqueous ammonia (25%) afforded the title compound (34 mg, 50%) as a light yellow solid. MS: m/e: 373.3 [M+H]+.