Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[O:33])/[C:27](O)=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:39]1([CH:45]([O:52][C:53]([C:55]2[N:56]3[C@H:59]([S:60][CH2:61][C:62]=2[CH2:63][S:64][C:65]2[N:70]4[N:71]=[C:72]([C:74]([O:76][CH:77]([C:84]5[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=5)[C:78]5[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=5)=[O:75])[N:73]=[C:69]4[N:68]=[C:67]([CH3:90])[CH:66]=2)[C@H:58]([NH2:91])[C:57]3=[O:92])=[O:54])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:39]1([CH:45]([O:52][C:53]([C:55]2[N:56]3[C@H:59]([S:60][CH2:61][C:62]=2[CH2:63][S:64][C:65]2[N:70]4[N:71]=[C:72]([C:74]([O:76][CH:77]([C:84]5[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=5)[C:78]5[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=5)=[O:75])[N:73]=[C:69]4[N:68]=[C:67]([CH3:90])[CH:66]=2)[C@H:58]([NH:91][C:27](=[O:28])/[C:26](/[C:24]2[N:25]=[C:21]([NH:20][C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:22][CH:23]=2)=[N:30]\[O:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[C:57]3=[O:92])=[O:54])[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)/C(=N\OC(=O)c1ccco1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4ccco4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: -30 °C
Reaction time: 9 h
Yield: 73.8 %

Procedure:
The product obtained in Example 29 (3.1 g) and the product obtained in Example 15 (4.3 g) were dissolved in anhydrous dichloromethane (200 ml) with stirring, the faint yellow solution was cooled to -30° C., and a solution of dicyclohexylcarbodiimide (1.2 g) in anhydrous dichloromethane (30 ml) was dropwise added over a period of five minutes. The resulting faint yellow solution was allowed to stand at 0° C. for nine hours, the colorless crystals separated were removed by filtration, and the filtrate was washed with 50 ml of 1N aqueous citric acid, 50 ml of saturated sodium bicarbonate solution and 80 ml of saturated sodium chloride solution in that order and dried over anhydrous sodium sulfate. The dried filtrate was concentrated in vacuo, the yellow, viscous residue (6.8 g) was purified by silica gel column chromatography using ethyl acetate/n-hexane as eluent, yielding 5.3 g of the objective compound as faint yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>>[CH3:21][CH:22]1[NH:23][CH2:24][CH2:25][N:26]([C:2]2[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27]1
Reactant: CC1CNCCN1
Reactant: COc1ccccc1OCC(C)Oc1nccnc1Cl
Product: COc1ccccc1OCC(C)Oc1nccnc1N1CCNC(C)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and 2-methylpiperazine (260 mg, 2.6 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (65%) of the title product. HRMS m/z calcd for C19H26N4O3 (M)+ 358.2005, found 358.2018. Anal. (C19H26N4O3) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][C:22]([C:24]2([OH:37])[CH2:29][CH2:28][CH:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:5][C:4]1[CH:6]=[C:7]([C:19]2[S:23][C:22]([C:24]3([OH:37])[CH2:29][CH2:28][CH:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CCC(O)(c2ncc(Br)s2)CC1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N)cc(-c2cnc(C3(O)CCC(C(=O)OC(C)(C)C)CC3)s2)c1
Temperature: 100 °C

Procedure:
To a flask containing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.6 g, 6.96 mmol), the product of Step 2 (2.52 g, 6.96 mmol), dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (0.33 g, 0.70 mmol), Pd2(dba)3 (0.32 g, 0.35 mmol), cesium carbonate (6.80 g, 20.9 mmol) was added a degassed mixture of dioxane (23 mL) and water (2.3 mL). The solution was evacuated and then purged with argon 5 times and then heated at 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate. MS ESI: [M+H]+ m/z 389.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:62]([NH:64][C:65]3([CH3:68])[CH2:67][CH2:66]3)=[O:63])=[CH:41][N:42]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.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:32][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])[N:8]=[C:7]2[C:34]1[N:39]=[C:38]2[C:40]([C:62]([NH:64][C:65]3([CH3:68])[CH2:67][CH2:66]3)=[O:63])=[CH:41][N:42]([C:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:37]2=[N:36][CH:35]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Reactant: CC1(NC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Br)nc23)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC2(C)CC2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 80 °C
Yield: 76.5 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (200 mg, 0.36 mmol) and 2-bromo-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (250 mg, 0.43 mmol) in DMF (10 mL) were added CuI (18 mg, 0.08 mmol) and Pd(PPh3)4 (14 mg, 0.014 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4 concentrated under reduced pressure to afford 2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (200 mg, 47%), material used in the next step without further purification. LCMS: (M+H)+=726; (M+Na)+=748.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([N:14]1[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([NH:26][O:27]C4CCCCO4)=[O:25])[CH:20]=3)[CH2:15]1)=[O:13])=[CH:6]2.Cl>C(O)(C)C>[OH:27][NH:26][C:24]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:12]([C:7]1[NH:8][C:9]3[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[O:13])[CH2:23][CH2:22]2)=[O:25]
Reactant: COc1ccc2[nH]c(C(=O)N3CCc4cc(C(=O)NOC5CCCCO5)ccc4C3)cc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2[nH]c(C(=O)N3CCc4cc(C(=O)NO)ccc4C3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A mixture of 45 mg of 2-[(5-methoxy-1H-indol-2-yl)carbonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 3 ml isopropanol and 3 ml of an aqueous, 0.1 N hydrochloric acid is stirred overnight at ambient temperature. The reaction mixture is evaporated and the residue is treated with acetonitrile. The resulting solid is collected and dried. 25 mg of a colorless solid are obtained with mp 156° C. MH+=366.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](O)([CH3:17])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:15][CH3:16])([CH3:14])[CH2:8]2.[H][H]>CO.S(=O)(=O)(O)O.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH3:17])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:15][CH3:16])([CH3:14])[CH2:8]2
Reactant: CCC1(C)Cc2ccc(C(C)(O)C(=O)OC)cc2C1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC1(C)Cc2ccc(C(C)C(=O)OC)cc2C1

Procedure:
A solution of 8 g of 2-ethyl-α-hydroxy-2,α-dimethyl-5-indanacetic acid methyl ester in 100 cc of methanol and 8 cc of concentrated sulphuric acid is hydrogenated at 40° to 45° and a hydrogen pressure of 4 atmospheres with the addition of 0.8 g of platinum(IV) oxide. After the take up of the theoretic amount of hydrogen, the solution is filtered, diluted with a 5% sodium bicarbonate solution and extracted with ether. The extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting oily title compound is purified by distillation. B.P. 138°-140° at 0.3 mm of Hg.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:22][CH2:23][CH2:24]Cl)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:13]([O:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:22][CH2:23][CH2:24][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Temperature: 25 °C
Yield: 36 %

Procedure:
4-phenyl piperidin (0.21 g, 1.2 mmol), compound 19 (0.3 g, 0.86 mmol), KI (0.43 g, 2.59 mmol) and K2CO3 (0.59 g, 4.3 mmol) were added to 50 mL CH3CN, and the solution was refluxed under argon atmosphere for 12 h. After cooling to room temperature, the inorganic salts were filtered, and the filtrate was evaporated to dryness. The residue was redissolved in CH2Cl2 and chromatographed on a silica gel TLC plate that was developed with the following eluents: 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as yellow oil (36% yield). 1H NMR (CDCl3) δ 8.492 (dd, 1H, Ar), 7.619 (ddd, 1H, Ar), 7.571 (t, 2H, Ar), 7.272 (t, 2H, Ar), 7.203 (d, 2H, Ar), 7.167 (t, 1H, Ar), 7.107 (m, 2H, Ar), 7.024 (t, 2H, Ar), 3.770 (s, 2H, —CH2—), 3.695, (s, 2H, —CH2—), 3.003 (d, 2H, —CH2—), 2.524 (t, 2H, —CH2—), 2.459 (m, 1H, —CH—), 2.367 (t, 2H, —CH2—), 2.01 (ddd, 2H, —CH2—), 1.783 (m, 6H), 1.359 (s, 9H, —C(CH3)3). Mass Spec.=472.34 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:29])=[C:22]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)[CH:21]=1
Reactant: CC(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Reactant: OB(O)c1cc(Cl)ccc1O
Product: CC(=O)N(Cc1ccccc1)c1ncc(-c2cc(Cl)ccc2O)cn1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.16 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1)=[O:30]
Reactant: CCOC(=O)CCCCCCCc1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCCCCCCC(=O)O)cc1

Procedure:
By the reaction of ethyl 7-[4-(2-aminoethyl)-phenyl]-heptane-carboxylate hydrochloride (m.p. 137°-139° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained 7-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-heptane-carboxylic acid; m.p. 103°-106° C., after recrystallization from diethyl ether.
Reaction SMILES: C(O[Si:5]([CH3:8])([CH3:7])[CH3:6])(=O)C.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11]>CCCCCC>[C:9]([O:14][Si:5]([CH3:8])([CH3:7])[CH3:6])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)O
Reactant: CC(=O)O[Si](C)(C)C
Solvent: CCCCCC
Product: C=C(C)C(=O)O[Si](C)(C)C

Procedure:
20 ml of acetoxytrimethylsilane and 11.4 ml of commercial methacrylic acid (ATOFINA Norsocryl® MAA) in 100 ml of hexane are mixed and heated. Azeotropic distillation of acetic acid affords trimethylsilyl methacrylate.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1>[Cl:1][CH2:2][C:3]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1CCNC1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of mL 2-chloroacetyl chloride (1.409 mL, 17.71 mmol) and THF (50 mL) was cooled to 0° C. and pyrrolidine (1.259 g, 17.71 mmol) was slowly added and stirred at ambient temperature for 3 hours. Partitioned between CH2Cl2 and water, and the organic layer was separated, dried, filtered, and concentrated to give the title compound (1.73 g, 66.19% yield) as a clear oil.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:7]1[CH2:8][CH2:9][N:4]([CH3:3])[CH:5]([CH2:10][OH:11])[CH2:6]1)[CH3:18]
Reactant: CN1CCNCC1CO
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCN(C)C(CO)C1

Procedure:
A mixture of (1-methyl-2-piperazinyl)methanol dihydrochloride (500 mg, 2.46 mmol), ethyl bromoacetate (410 mg, 2.46 mmol), K2CO3 (1.02 g, 7.38 mmol) and MeCN (15 mL) were heated to reflux for 18 h. After cooling, the mixture was filtered and concentrated in vacuo. The title compound was isolated as a colourless oil (525 mg, 98%) and used without further purification. 1H NMR (300 MHz, CDCl3): 1.25 (3H, t, J 7.0), 2.35 (3H, s), 2.35-2.59 (4H, m), 2.76-2.90 (3H, m), 3.19 (2H, m), 3.44 (1H, dd, J 11.3, 2.0), 3.87 (1H, dd, J 11.3, 4.0), 4.15 (2H, q, J 7.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([OH:11])=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:7][C:6]=12.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([OH:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2c(Br)cnn2c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Ethyl 3-bromo-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (Journal of Medicinal Chemistry, vol. 25, p. 235, 1982) (11.0 g, 38.5 mmol) was dissolved in ethanol (134 mL), 2 mol/L aqueous sodium hydroxide solution (134 mL, 269 mmol) was added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled to room temperature, and ethanol was evaporated under reduced pressure. 2 mol/L Hydrochloric acid (140 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, and washed with water (100 mL) and 2-propanol (50 mL) to give the title compound (9.9 g, 99%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[N:16][C:15]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[N:23][C:14]1=2)C1C=CC=CC=1>C(OCC)(=O)C.ClCCl.[O-2].[O-2].[Mn+4]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[N:16][C:15]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[N:23][C:14]1=2
Reactant: COc1ccc2ncc(=O)n(CCCCOCc3ccccc3)c2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCCCO)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
To a solution of 4-[4-(benzyloxy)butyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (847 mg, 2.5 mmol) in ethyl acetate (20 ml) 20% palladium hydroxide (400 mg) was added and the catalytic hydrogenation was carried out at room temperature for 90 minutes. After removing the catalyst by filtration, the solvent was removed under reduced pressure, the obtained residue was dissolved in dichloromethane (20 ml) to which manganese dioxide (1.09 g, 12.5 mmol) was then added, and the mixture was stirred overnight at room temperature. After removing manganese dioxide by filtration, the solvent of the filtrate was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 548 mg (88%) of the title compound in the form of a light brown solid.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12].O>C1CCCCC1>[CH3:7][NH:8][CH2:9][CH2:10][CH:11]=[N:12][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C=O
Reactant: CNCCCN
Solvent: C1CCCCC1
Solvent: O
Product: CNCCC=NCC(C)(C)C

Procedure:
75.0 g (0.87 mol) of pivalaldehyde are added dropwise to a solution of 76.7 g (0.87 mol) of 3-methylaminopropylamine in 200 ml of dry cyclohexane. After the addition, the solution is heated under reflux in a water separator for 3 hours. The solvent is then removed in a rotary evaporator and the residue is distilled. Boiling point: 69° C./67 mbar
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:30]3[CH2:31][CH2:32][CH:27]([F:26])[CH2:28][CH2:29]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC1CCNCC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC2CO2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC(O)CN2CCC(F)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
A solution of 0.080 g (0.22 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one (example 166A) in 0.5 ml of MeOH was treated with 0.038 (0.26 mmol) of 4-fluoropiperidine hydrochloride and 0.15 ml (1.08 mmol) of Et3N in 0.5 ml of MeOH. The reaction was stirred for 24 h at RT, partitioned between aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phase was dried over Na2SO4 and evaporated to give after flash silica gel column (CH2Cl2/MeOH 98:2) 0.0099 g (10%) of the title compound as white foam. MS: 471.9 (MH+, 2Cl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].S(Cl)(Cl)=[O:33]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=[O:33])=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(=O)O)c(F)c1
Reactant: O=S(Cl)Cl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1c1ccc(C(=O)O)c(F)c1
Reaction time: 15 h

Procedure:
A solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (50 mg, 0.11 mmol) in thionyl chloride (0.5 mL, 67.7 mmol) was stirred at 90 deg C. for 15 h. The reaction mixture was concentrated under reduced pressure to dryness. Ice-water (20 mL) was added into the residue and the product was extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product, which was purified by reverse phase HPLC to yield 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoic acid. 1H NMR DMSO-d6 (FREE BASE): δ (ppm) 8.39 (d, 1H), 8.25 (s, 1H), 8.1 (d, 1H), 8.0 (t, 1H), 7.45 (d, 1H), 7.4 (d, 1H), 1.58 (s, 6H).
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO[CH2:27][CH2:28][OH:29].C(=O)=O.[Li+].CC([N-]C(C)C)C.[CH2:41]([N:48]1[CH2:52][C:51](C=O)=[CH:50][NH:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:41]([N:48]1[CH2:52][C:51]([CH2:27][CH:28]=[O:29])=[CH:50][NH:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOCCO
Reactant: O=CC1=CNN(Cc2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=CCC1=CNN(Cc2ccccc2)C1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of methoxymethyl-triphenyl-phosphonium chloride (2.06 g, 6.00 mmol) in dry THF (20 mL) cooled at −15° C. (ethyl glycol/dry ice) was added LDA (2.0 M in THF, 3.1 mL, 6.2 mmol) slowly. After the addition the mixture was stirred at −15° C. for 30 min, and a solution of 2-benzyl-1H-pyrazole-4-carbaldehyde (1.00 g, 5.37 mmol) (Werner, A., et al., Tetrahedron (1995) 51:4779-4800) in THF (15 mL) was added. The reaction mixture was stirred at room temperature for 16 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL) and CH2Cl2 (2×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2) to afford a colorless oil. The oil was dissolved in THF (3 mL) and aqueous HCl (4 N, 15 mL) was added. After being stirred for 72 h, the mixture was neutralized with saturated aqueous K2CO3, and extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (2:1 CH2Cl2/Et2O), affording (2-benzyl-1H-pyrazol-4-yl)-acet aldehyde as a colorless oil (0.548 g, 51%). 1H NMR(CDCl3) δ 3.56 (d, 2H, J=2.1 Hz), 5.29 (s, 2H), 7.21-7.24 (m, 2H), 7.28-7.39 (m, 4H), 7.45 (s, 1H), 9.70 (t, 1H, J=2.1 Hz).