Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([C:14]2[O:15][C:16]3[CH:23]=[CH:22][CH:21]=[C:20](O)[C:17]=3[C:18]=2[CH3:19])=O)=[CH:10][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([C:14]2[O:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]=2[CH3:19])=[CH2:1])=[CH:10][CH:9]=1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cccc(O)c12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)cc1)c1oc2ccccc2c1C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a suspension of potassium t-butoxide (448 mg; 4 mmoles) in tetrahydrofuran (25 mL) was added methyl-triphenylphosphonium bromide (1.07 gm; 3 mmoles). The mixture was stirred for a period of 2 hours. 2-(4-chlorobenzoyl)-3-methyl-4-hydroxy-benzofuran (286 mg; 1 mmole) in tetrahydrofuran (5 ml) was added rapidly and the mixture was stirred for an additional 30 minutes at room temperature. The mixture was poured into 10% citric acid solution (100 ml) and was extracted with ethylacetate. The organic phase was dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 210 mg (73%) of 2-(1-(4-chlorophenyl)vinyl)-3-methylbenzofuran as an oil.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10]([O:15]C)(=[O:14])[C:11]([CH3:13])=[CH2:12]>[O-2].[Ca+2].[Cl-].[Li+].COC1C=CC(O)=CC=1>[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: C=C(C)C(=O)OC
Agent: CCC(CO)(CO)CO
Agent: COc1ccc(O)cc1
Agent: [Ca+2]
Product: C=C(C)C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
775 kg of trimethylolpropane, 1018 kg of methyl methacrylate (MMA) and also 1433 kg of recycled MMA from Comparative Example 1, 0.123 kg of hydroquinone monomethyl ether as inhibitor and a mixture of 10 kg of calcium oxide and 2.5 kg of lithium chloride as catalyst are combined in a 6 m3 stirred tank reactor provided with agitator, steam heating, distillation column and condenser and the mixture is stirred while passing in air. To stabilize the column, a total of 151 kg of MMA containing 0.12 kg of hydroquinone monomethyl ether and 0.016 kg of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl in dissolved form are introduced into the column runback during the course of the reaction. The apparatus is heated to a temperature at the bottom of 100° C., with the column initially being operated under total reflux. As soon as the temperature at the top of the column drops below 70° C., the methanol/MMA mixture is taken off at a reflux ratio of 4:1. The MMA stock in the reactor is supplemented by introduction of equal parts of fresh MMA per part of methanol/MMA mixture taken off. A total of 1414 kg of MMA are in this way introduced over a period of 5 hours. Over a period of 8 hours, the reflux ratio is adapted to the decreasing formation of methanol to 27:1. A total of 1410 kg of methanol/MMA mixture are discharged. Above a temperature at the top of the column of 85° C., the methanol/MMA mixture is low in methanol and is collected in a separate vessel for reuse as raw material in the next batch. At a temperature at the bottom of 115° C., the reaction is complete and excess MMA is taken off under reduced pressure, with the pressure gradually being reduced to 100 mbar. When no more MMA distills off, the vacuum is broken. The contents of the tank, which comprise the catalyst-containing trimethylpropane trimethacrylate, are admixed with 18 kg of bleaching earth and 12 kg of aluminium silicate (Perlite) as filter aid and freed of the catalyst by washcoat filtration. The filtrate is fed into a continuous evaporator (area: 3.5 m2) having a rotating wiper system at a pressure of 18 torr and an evaporator temperature of 134° C. A total of 1830 kg of trimethylolpropane trimethacrylate are obtained from the bottom product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[C:6]([F:12])[CH:5]=1)=[O:3].[Br-].[Al+3].[Br-].[Br-]>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:12])[CH:5]=1)=[O:3]
Reactant: COc1ccc(C(C)=O)cc1F
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To 400 ml of dried toluene was added 20.4 g of 3-fluoro-4-methoxyacetophenone, which was uniformly stirred at room temperature and added with 66.1 g of anhydrous aluminum bromide over about 20 minutes. After the stirring at room temperature for 4 hours, the reaction mixture was poured into 600 ml of ice water. After the separation into two layers, the extraction with ether on aqueous layer was repeated two times, and then the organic layers were gathered, washed with water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and dried under a reduced pressure to obtain 17.45 g of a brown crystal. This crystal was recrystallized with toluene to obtain 16.53 g (yield: 88%) of a white crystal having a melting point of 127.0°-128.2° C.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>ClCCl>[C:2]1([C:1]([NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:11])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To an ice-bath cooled solution of benzoyl isocyanate (7.725 ml, 0.0525 Mol) in dichloromethane (400 ml) was added 4-amino-1-benzyl piperidine (10 g, 10.72 ml, 0.0525 Mol) dropwise. When the addition was complete the solution was allowed to stir at room temperature for 1 h then the solvent was removed by rotary evaporation. The residue was triturated with diethyl ether and collected by filtration to give the required product as a white solid 15.4 g (87%). Mp. 179°-180° C. 1H NMR (DMSO) δ 1.51 (2H, m), 1.86 (2H, m), 2.14 (2H, m), 2.69 (2H, m), 3.47 (2H, s), 3.65 (1H, m), 7.24-7.33 (5H, m), 7.50 (2H, t, J=7.9 Hz), 7.61 (1H, t, J=7.9 Hz), 7.96 (2H, d, J=7.9 Hz), 8.69 (1H, d, J=7.8 Hz), 10.67 (1H, br s); MS (CI) m/e 338 [MH]+. Anal. Found C, 70.99; H, 6.86; N, 12.41. C20H23N3O2 requires C, 71.19; H, 6.87; N, 12.45%.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][Si](C(C)C)(C(C)C)C(C)C)=[CH:30][CH:29]=2)=[CH:23][C:22]=1[C@:46]1([O:64][C@H:63]([CH2:65][O:66]C(=O)C)[C@@H:58]([O:59]C(=O)C)[C@H:53]([O:54]C(=O)C)[C@H:48]1[O:49]C(=O)C)[OH:47].[OH-].[K+].Cl>O1CCCC1.CO>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[CH:32][CH:33]=2)=[CH:23][C:22]=1[C@:46]1([O:64][C@H:63]([CH2:65][OH:66])[C@@H:58]([OH:59])[C@H:53]([OH:54])[C@H:48]1[OH:49])[OH:47]
Reactant: COc1ccc(Cc2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)cc1[C@@]1(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Cc2ccc(OC)c([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.78 mL of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 0.55 g 1-methoxy-2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-4-(4-triisopropylsilylethynyl-benzyl)-benzene in 2 mL tetrahydrofuran. The solution is stirred for 30 min at ambient temperature and then diluted with 4 mL methanol. 0.85 mL of 4 M potassium hydroxide solution are added and the resulting solution is stirred for an additional 30 min at ambient temperature. The reaction solution is neutralized with 1 M hydrochloric acid and concentrated in vacuo. The residue is combined with brine and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is evaporated. The residue is chromatographed over silica gel (dichloromethane/methanol 9:1->2:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:40][CH3:41].O>CN(C=O)C>[CH2:40]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:10])[CH3:41]
Reactant: CCI
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
To a suspension of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.743 mmol, 340 mg) and sodium bicarbonate (5.94 mmol, 499 mg) in DMF (3.8 mL) was added iodoethane (5.94 mmol, 0.475 mL) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (100 mL) and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine solution (80 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to obtain 335 mg (93% yield) of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl ester as a crystalline white solid: mp 218-219° C. ES-HRMS m/e calcd for C25H25F2N3O5 (M+Na) 508.1654, found 508.1660.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH3:8])[CH:7]=1.[CH3:10][N:11](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[N:11])=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(F)ccc1C#N
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5-Fluoro-2-iodotoluene (3 g, 12.7 mmol) was stirred in DMF (40 mL) under argon and Zn(CN)2 (1.94 g, 16.5 mmol) and Pd(PPh3)4 (1.47 g, 1.27 mmol) were added. The reaction was stirred at 80° C. for 1.5 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2-SO4. The solvent was removed under reduced pressure to afford a yellow solid (2.90 g), confirmed by GC MS.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[N:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][C:14]=1[CH2:13][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Sc1ncnc2ccccc12
Product: c1ccc2[nH]c(CSc3ncnc4ccccc34)nc2c1
Yield: 56.5 %

Procedure:
The title compound(2.5 g) was prepared from 4-mercaptoquinazoline(6.0 g) and 2-chloromethylbenzimidazole (2.52 g).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])[CH2:5][CH2:4][O:3]1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:21]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([O:19][CH3:18])[N:21]=[C:22]([NH:28][C:29]([NH:17][S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]2[CH2:5][CH2:4][O:3][C:2]2=[O:1])(=[O:15])=[O:16])=[O:30])[N:23]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1C=C1CCOC1=O
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C=C2CCOC2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a stirred suspension of 0.09 g (0.0004 mol) of the product of Example 3 and 0.15 g (0.0005 mol) of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 1 mL dry acetonitrile under nitrogen was added dropwise 0.08 mL (0.08 g, 0.0005 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature for 30 min and was then diluted with water and acidified with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed well with water and ether to yield 0.1 g (64%) of the title compound: m.p. 185°-190° (gas evolution); IR (nujol) 3180 (br), 1755, 1740, 1710, 1700, 1610, 1560, 1355, 1165 cm-1 ; NMR (CDCl3, 200 MHz) δ 3.05 (2H, m), 4.29 (2H, t, J=7 Hz), 3.99 (6H, s), 5.83 (1H, s), 7.2 (NH, s), 7.4-7.8 (3H, m), 8.1 (1H, m), 8.12 (NH, s), 8.14 (1H, m).
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([N:49]3[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]3)=[O:48])=[CH:43][CH:42]=2)[CH:13]=[C:14]([Cl:40])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23]2)[C:18]1=[O:39]>C1COCC1>[Cl:40][C:14]1[CH:13]=[C:12]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([N:49]3[CH2:54][CH2:53][C:52]([F:55])([F:56])[CH2:51][CH2:50]3)=[O:48])=[CH:45][CH:46]=2)[CH:11]=[C:10]([Cl:9])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:18]1=[O:39]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Add water (60 mL) and TFA 20 mL) to a solution of (R)-3-[3,5-dichloro-4′-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one in THF (60 mL). Stir the mixture at room temp for 12 hours. Partition the reaction with ethyl acetate (200 mL) and sodium bicarbonate (sat. solution, 150 mL), separate the organic layer, extract the aqueous with another 200 mL of ethyl acetate, and combine the organic solutions. Dry over sodium sulfate, filter and concentrate. Dissolve the residue in 40 mL of dichloromethane and load on a Biotage Si 65M 1385-1 column, flash with ethyl acetate for 30 minutes, switch to 8% methanol in dichloromethane to afford 8.02 grams (97%) of the desired product as white solid. MS (m/z): 566 (M+).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[S:19][CH:20]=[C:21]([C:23](O)=[O:24])[N:22]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[N:22]=[C:18]([C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[S:19][CH:20]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1csc(-c2cccs2)n1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1csc(-c2cccs2)n1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-(2-thienyl)-1,3-thiazole-4-carboxylic acid (Maybridge) according to methods A and C; yield 103 mg, 0.25 mmol (62%): 1H NMR (300 MHz, methanol-d4) δ 2.04-2.32 (m, 3H), 2.51 (s, 2H), 2.51 (s, 2H), 3.46-3.62 (m, 4H), 3.82 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.18 (dd, J=5, 4 Hz, 1H), 7.65 (dd, J=5, 1 Hz, 1H), 7.64 (dd, J=5, 1 Hz, 1H), 7.72 (dd, J=4, 1 Hz, 1H), 8.21 (s, 1H); MS (DCI/NH3) m/z 346 (M+H)+; Anal. C17H19N3OS2.2HCl: C, H, N.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Product: CC1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 97.7 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethyl amide (0.142 g, 0.485 mmol) and (±)-4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.156 g, 0.533 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 97%) (following SiO2 chromatography, eluting with 0-3% MeOH/dichloromethane). MS(ESI) m/z 549.3 (M+H)+
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O>CS(C)=O>[N:29]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[4-(2-Tosyloxyethoxy)Benzyl]-2,4-Thiazolidinedione (12.5 g) in dry Dimethylsulphoxide (80 ml) was added sodium azide (2 g) in one portion. The mixture was stirred at ambient temperature for 18 hours and the resulting solution added to water (250 ml). The aqueous solution was extracted with dichloromethane (2×300 ml) and the combined organic phases were washed with water (3×300 ml), dried (MgSO4), filtered and evaporated to give the title compound as an oil which was used in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>[OH-].[Na+].CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccccc1COc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1COc1cccc(Br)c1
Yield: 107.6 %

Procedure:
Methyl 2-(3-bromophenoxymethyl)benzoate (34 g) was refluxed in a mixture of 100 mL of 10% sodium hydroxide and 200 mL of methanol for three hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was then acidified with concentrated hydrochloric acid. Extracting the acidic solution with ethyl acetate and then concentration of the organic layer gave 2-(3-bromophenoxymethyl) benzoic acid (35 g) m.p. 158°-159° C. pmr (CDCL3) 6: 8.10 ()m, 1H, H6), 6.84-7.74 (m, 7H, aromatic H), 6.16 (br s, 1H, CO2H), 5.49 (s, 2H, ArCH2O).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC([C:47]2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3[N:48]=2)=CC=1.COC(=O)C1C=CC(N)=C(C#N)C=1.C(N(CC)C(C)C)(C)C>>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([C:47]#[N:48])[CH:6]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: COC(=O)c1ccc(N)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C#N)c1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, 4-amino-3-cyano-benzoic acid methyl ester and N,N-diisopropylethylamine as a base.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:4](=[O:12])[CH2:5][CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][CH3:11])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:13][C:2]([CH3:3])([CH:4]([OH:12])[CH2:5][CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][CH3:11])[CH3:1]
Reactant: CC=CC=CCCC(=O)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC=CC=CCCC(O)C(C)(C)C
Yield: 47.6 %

Procedure:
According to the procedure described in Example 3, by reducing 16.2 g of 2,2-dimethyl-6,8-decadien-3-one with 3.4 g of lithium aluminium hydride in 250 ml of dry ether there are obtained 17 g of crude product which gave 7.8 g of pure 2,2-dimethyl-6,8-decadien-3-ol by fractional distillation.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]12)=O)(C)(C)C.Cl>CO>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([NH:8][CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(C(=O)OC(C)(C)C)[C@H]2C1
Agent: Cl
Solvent: CO
Product: CN1C[C@H]2CCN[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Example 7A (20.8 g, 0.86 mole) in methanol (450 ml) was added aqueous 3N HCl (300 ml). The mixture was stirred at room temperature overnight, then concentrated to dryness at 30° C. under vacuum. The residue was treated with aqueous 1N NaOH to obtain a pH of 9-10. The mixture was concentrated to dryness. The crude material was purified by chromatography (eluting with a mixture of 10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 4.12-4.17 (m, 1H) 3.31-3.43 (m, 1H) 3.19-3.30 (m, 1H) 3.12 (d, J=11.53 Hz, 1H) 2.88-3.01 (m, 1H) 2.69 (dd, J=9.49, 2.37 Hz, 1H) 2.40-2.52 (m, 2H) 2.33 (s, 3H) 2.12-2.28 (m, 1H) 1.82-1.95 (m, 1H). MS: (M+H)+=127.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:18][NH2:19]>CN(C=O)C>[CH3:18][NH:19][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]=1[F:5]
Reactant: CN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Thionyl chloride (2.38 g, 20 mmol) was added slowly to a solution of 2-fluoro-4-nitrobenzoic acid (2.97 g, 16 mmol) in DMF (50 ml) cooled at -5° C. The mixture was stirred for an additional 1 hour at −5° C. Methylamine (0.62 g, 20 mmol; freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 hour. Ethyl acetate (300 ml) was added to the mixture, which was washed with brine (3×150 ml). The organic layer was dried over MgSO4, and concentrated to yield N-methyl-2-fluoro-4-nitrobenzamide (52a) (2.89 g, 14.6 mmol, 91%) as a yellow solid. 1H NMR (Acetone d6, 400 MHz) δ 3.05 (d, J=4.3 Hz, 3H), 6.31 (dd, J=13.5, 2.1 Hz, 1H), 6.40 (dd, J=8.5, 2.1 Hz, 1H), 7.64 (dd, J=8.6, 8.6 Hz, 1H).