Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:10]([CH3:16])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[C:13](=[O:14])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:17])[N:10]([CH3:16])[C:11]=1[CH3:15]
Reactant: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)n1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)c(-c2ccc(Cl)cc2)c(C)n1C

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-1,2,6-trimethylpyridin-4-one (0.5 g) in acetic acid (5 ml) was added dropwise a solution of bromine (0.1 ml) in acetic acid (1 ml). After 5 min the mixture was poured into water. The solid was filtered off, washed with water and recrytallised from ethanol (10 ml) to give the desired compound (0.25 g), m.p. 264°-266°, NMR δH (CDCl3) 7.3-7.4 (2H, m), 7.05-7.2 (2H, m), 6.95-7.12 (4H, m), 3.65 (3H, s), 2.7 (3H, s), 2.2. (3H, s).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CC1C=CC(S(O[CH2:42][C@@H:43]2[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[O:44]2)(=O)=O)=CC=1.[I-].[Na+].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][C:45]1([CH3:49])[O:44][C@H:43]([CH2:42][N:21]2[CH2:22][CH2:23][C:17]3[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])=[N:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=4)=[N:19][C:18]=3[CH2:20]2)[CH2:47][O:46]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C[C@@H]2COC(C)(C)O2)C3)cc1
Yield: 64.7 %

Procedure:
A solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (jk) (270 mg, 0.69 mmol), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (377 mg, 132 mmol), sodium iodide (104 mg, 0.69 mmol), DIPEA (0.48 mL, 2.8 mmol), and DMF (1.0 mL) was heated at 110° C. for 22 h. The mixture was partitioned between ethyl acetate and sat. NaHCO3. The phases were separated, and the aqueous layer extracted with ethyl acetate (2×). The combined organic phases were dried over Na2SO4, filtered and concentrated onto Celite, and the residue chromatographed: ISCO 12 g column 0-20% IPA in DCM to afford 228 mg (64%) of the title compound jz as an off-white solid: LC-MS: m/z=+511 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>C(O)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)sc(N=Cc2cccs2)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.5 %

Procedure:
In a 250 mL flask comprising 50 ml absolute ethanol, was dissolved 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester (470 mg, 5.0 mmol) followed by 2-thiophene carboxaldehyde (646 mg, 2.5 mmol). After the addition of one drop of acetic acid, the solution was stirred at room temperature for 4 days. The solvent was then removed from the resulting orange solution and the residue was purified by flash chromatography (SiO2) using 20% ethyl acetate/hexane to afford the title compound as a yellow solid (454 mg, 52%). M.p.=145°-147° C. 1H-NMR (200 MHz, [D] chloroform): δ=9.94 (s, 1H), 8.06 (s, 1H), 7.20 (t, 1H), 7.18 (d, 1H), 7.12 (m, 1H), 7.02 (m, 1H), 4.41 (t, 2H), 4.24 (q, 2H), 1.48 (t, 3H), 1.29 (t, 3H). 13C-NMR (50 MHz, [D] chloroform): δ=164.5, 159.9, 145.9, 142.7, 134.0, 131.2, 130.2, 127.9, 102.9, 61.6, 60.3, 14.5, 14.3. FAB-MS: m/z 351.8 ([M]+, 100%). Anal. calc. for C15H16N2O4S2 (352.06): C, 51.12, H, 4.58, N, 7.95, O, 18.16, S, 18.20 found: C, 51.21; H, 4.63; N, 7.77, S, 17.81. λmax (DMSO)=402 nm. ε (DMSO)=3.6×104 M−1 dm−1; λmax (acetonitrile)=408 nm, λfl(acetonitrile)=604 nm.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[CH3:20][O:21][NH2:22]>>[CH3:20][O:21][N:22]=[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[CH:11][CH:12]=1)[CH3:17]
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Reactant: CON
Agent: Cl
Product: CON=C(C)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 78) and 2.4 mmol of O-methylhydroxylamine hydrochloride are treated as described in Example 92.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)C>CC(O)C>[N:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:13][CH2:14][CH:9]([C:7]([NH:2][NH2:3])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C

Procedure:
Hydrazine hydrate (61.4 ml, 1.265 mol) was charged to a propan-2-ol solution of 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (0.253 mol, 5 ml/g)(see reference Farmaco, 1993, 48(10), 1439), before heating under reflux for 18 hours. The mixture was cooled to room temperature and then to 10° C. and the product, a white solid, was collected by filtration (44.5 g).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:10]([CH:11]=O)[C:9]=1[SH:19])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:20]=[C:21]1[C:29]([CH3:31])([CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:32]>CC(=O)CC>[C:1]([O:6][CH2:7][C:8]1[C:9]2[S:19][C:21]3([C:29]([CH3:31])([CH3:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]3[CH3:32])[CH:20]=[CH:11][C:10]=2[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: C=C(C)C(=O)OCc1cc([N+](=O)[O-])cc(C=O)c1S
Solvent: CCC(C)=O
Product: C=C(C)C(=O)OCc1cc([N+](=O)[O-])cc2c1SC1(C=C2)N(C)c2ccccc2C1(C)C
Yield: 72.7 %

Procedure:
In 120 ml of 2-butanone were dissolved 14.1 g of 3-methacryloxymethyl-5-nitrothiosalicylaldehyde and 8.7 g of 2-methylene-1,3,3-trimethylindoline and the mixture was refluxed in a nitrogen atmosphere for 20 hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 15.9 g of 8-methacryloxymethyl-6-nitro-1',3',3'-trimethylspiro[2H-1-benzothiopyran-2,2'-indoline] as light yellow crystals (Yield 73%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:7][N:6](C(OOC(C)(C)C)=O)[C@@H:5]([C:16]([O-:18])=[O:17])[CH2:4]1.Cl>C1COCC1>[CH3:1][O:2][C@H:3]1[CH2:7][NH:6][C@@H:5]([C:16]([OH:18])=[O:17])[CH2:4]1
Reactant: CO[C@@H]1C[C@H](C(=O)[O-])N(C(=O)OOC(C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CO[C@H]1CN[C@@H](C(=O)O)C1
Reaction time: 3 h

Procedure:
10.3 g (48.9 mmol) 1-tert.butoxy (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylate are dissolved in 50 ml THF, 50 ml 6N hydrochloric acid (300 mmol) are added and the mixture is stirred for three hours. The reaction mixture is evaporated to dryness i.vac.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:14])[CH3:13])=[C:4]([C:8](O)=[O:9])[NH:5][C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1>>[Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:14])[CH3:13])=[C:4]([C:8]([NH:27][C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[O:9])[NH:5][C:6]=1[Br:7]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(C(=O)O)[nH]c(Br)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)[nH]c(Br)c1Br
Yield: 19 %

Procedure:
Prepared by the method described in Example 115 from 4,5-dibromo-3-(1-methylethoxy)-1H-pyrrole-2-carboxylic acid (1.4 g, 0.004 moles), 1,1'-carbonyldiimidazole (1.2 g, 0.007 moles), and 5-aminotetrazole (0.6 g, 0.007 moles). Recrystallization from acetonitrile gave the product (0.3 g); mp 194°-196° C.
Reaction SMILES: C(C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC([Cl:29])=CC=3)=O)=CC=2F)C=CN=1)(=O)N.[ClH:35].[NH2:36][C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:67]=[CH:66][CH:65]=[CH:64][C:52]=3[C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59](F)=[CH:58][C:57]=3F)=[O:54])=[CH:46][C:45]=2[F:68])[CH:40]=[CH:39][N:38]=1>>[ClH:29].[NH2:36][C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:67]=[CH:66][CH:65]=[CH:64][C:52]=3[C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59]([Cl:35])=[CH:58][CH:57]=3)=[O:54])=[CH:46][C:45]=2[F:68])[CH:40]=[CH:39][N:38]=1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(Cl)cc3)cc2F)ccn1
Agent: Cl
Product: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(Cl)cc3)cc2F)ccn1
Yield: 25 %

Procedure:
2-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(4-chlorophenyl)nicotinamide (0.088 g, 0.18 mmol) was converted to the title compound (0.022 g, 25%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 10.65 (s, 1H), 10.40 (s, 1H), 8.36 (dd, 1H, J=4.9, 1.6 Hz), 8.25-8.28 (m, 1H), 8.11 (dd, 1H, J=13.6, 2.4 Hz), 7.71-7.92 (m, 5H), 7.29-7.45 (m, 4H), 6.98 (dd, 1H, J=7.7, 4.9 Hz), 6.65 (dd, 1H, J=7.3, 2.5 Hz), 6.13 (d, 1H, J=2.4 Hz);
Reaction SMILES: Br[C:2]1[N:11]2[C:5]([CH2:6][N:7]([CH3:17])[CH2:8][C:9]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=32)=[N:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.S1(CCCC1)(=O)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]3[C:2]([N:18]4[CH2:23][CH2:22][C:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20][CH2:19]4)=[N:3][N:4]=[C:5]3[CH2:6][N:7]([CH3:17])[CH2:8][C:9]=2[CH:15]=1
Reactant: CN1Cc2cc(Cl)ccc2-n2c(Br)nnc2C1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S1(=O)CCCC1
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC3(CC2)OC(=O)c2ccccc23)C1
Temperature: 160 °C
Reaction time: 20 h
Yield: 14.3 %

Procedure:
A mixture of 1-bromo-8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene (50 mg, 0.16 mmol), tetrabutylammonium bromide (10 mg, 0.031 mmol) and 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (65 mg, 0.32 mmol) in sulfolane (0.5 ml) was stirred for 20 h at 160° C. The reaction mixture was poured on water and extracted with tert-butyl methyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Residual sulfolane was evaporated by kugelrohrdistillation (120° C., 1-2 mbar). Preparative HPLC with n-heptane/2-propanol (70:30) as eluent gave the title compound (10 mg, 14%) as light yellow solid. MS m/e: 436 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:16][CH3:17])[C:9]1=[O:18])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([N:10]1[CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[NH:8][C:9]1=[O:18])[CH3:17]
Reactant: CCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)NC2CCCC21
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.6 %

Procedure:
To a solution of (3aSR,6aRS)-3-methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 2) (1.60 g, 6.29 mmol) in 15 ml of dichloromethane was added trifluoroacetic acid (5.74 g, 3.9 ml, 50.3 mmol, 8 equiv.) and the yellow solution was stirred for 15 h at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution and the pH of the aqueous phase was set to 9. After workup with dichloromethane/water, the organic phases were dried, filtered and concentrated in vaccuo to yield 0.801 g of a yellow oil, which directly used in the next step without further characterization.
Reaction SMILES: [NH2:1][C:2]1[N:32]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](Cl)=[O:40])[CH:34]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([CH:12]=2)[O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:39]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:40])[N:32]=3)[CH:9]=2)=[O:31])[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27])#[N:30]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Reactant: O=C(Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.469 mmol) in pyridine (5 mL) was added pyridine-3-carbonyl hydrochloride (212 mg, 1.19 mmol), and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (245 mg, 97%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:37][C:38]([CH3:45])([C:41]([F:44])([F:43])[F:42])[C:39]=1[CH3:40])#[N:34]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([CH3:45])([C:41]([F:44])([F:42])[F:43])[O:37][C:36](=[C:46]([C:47]#[N:48])[C:49]#[N:50])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84 %

Procedure:
In 10 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 730 mg (1.63 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 380 mg (1.5 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 19 hours and further stirred with heating at 50° C. for 6 hours. The solvent was evaporated off and the residue was washed with ethanol to give 860 mg of a dark reddish brown crystal (yield: 94.0%; mp: 184-185° C.)
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9]2[N:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)(=O)[CH2:2][CH3:3].B.C1COCC1>C1COCC1>[CH2:1]([N:5]1[CH2:8][CH:7]([C:9]2[N:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cn2)C1
Agent: B
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cn2)C1
Yield: 60.2 %

Procedure:
Following the same procedure as described in Example 46.6, N-[6-(1-propionyl-azetidin-3-yl)-pyridin-3-yl]-4-trifluoromethoxy-benzenesulfonamide (130 mg, 0.30 mmol) in THF (15 ml) was treated with 1M BH3.THF (3 ml). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provides the title compound (75 mg, 60%) as a light yellow oil.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH:11]=[O:12])[CH:8]=[N:9][CH:10]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([CH:11]([OH:12])[CH3:1])[CH:8]=[N:9][CH:10]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cncc(Br)c1
Temperature: 0 °C

Procedure:
Methylmagnesium bromide (1M in THF, 12 mL, 12 mmol) was added dropwise to a solution of 5-bromo-pyridine-3-carbaldehyde (1.85, 10 mmol) in dry THF (20 mL) at −78° C. The resulting mixture was slowly warmed up to 0° C. during a 2 hour period and then quenched by aq. satd. NH4Cl solution. After extraction with DCM, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title compound as a crude product (1.9 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28](=[O:32])[CH2:29][CH2:30][CH:31]=2)=[CH:23][CH:22]=1>CCOCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([OH:32])[CH2:29][CH2:30][CH:31]=[C:27]2[C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC=C1c1ccc(F)cc1
Reactant: CSc1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et2O cooled at −78° C., was added 22 niL of 1.7 M solution of t-BuLi in pentane (38 mmol) dropwise. The reaction mixture was stirred for 15 min at −78° C. and a solution of 2.23 g of 2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 mL of Et2O was added. After stirring for 15 min at −78° C., the reaction mixture was warmed to 0° C., and quenched with 50 mL of sat. NH4Cl. The product was extracted with 100 mL EtOAc, dried over Na2SO4, and purified by flash chromatography, eluted with 4:1 hexane/EtOAc to give 3.4 g of the desired product.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:10]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)=[O:12])[C:6](OC)=O.B.[Na].Cl.C([OH:41])C>>[CH3:1][S:2][CH2:3][CH2:4][C:5]([CH3:6])([N:10]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)=[O:12])[OH:41]
Reactant: COC(=O)C(CCSC)N(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: CCO
Agent: B
Agent: Cl
Agent: [Na]
Product: CSCCC(C)(O)N(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Reaction time: 2 h

Procedure:
In 80 ml of ethanol is dissolved 1.6 g of 6-{4-[N-(3-methylthio-1-methoxycarbonylpropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}carbostyril. Thereto is added 3.2 g of sodium boron hydride. The mixture is stirred for 2 hours at 50°-60° C. The reaction mixture is neutralized with diluted hydrochloric acid and concentrated. The residue is extracted with a mixture of chloroform and methanol (10:1). The extract is purified by means of a silica gel column chromatography (eluant; chloroform:methanol=20:1). The resulting residue is recrystallized from a mixed solvent of dichloromethane-ethyl acetate-diethyl ether to obtain 0.78 g of 6-{4-[N-(3-methylthio-1-hydroxy-methylpropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}carbostyril.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:38][CH3:39])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:21]#[N:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:40]O.[OH-].[K+].O>C(O)C>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=1)[CH2:23][N:20]([CH2:19][C:9]1[CH:10]=[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]2=[N:13][C:8]=1[N:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:38][CH3:39])[C:21]([NH2:22])=[O:40]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Reactant: OO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O)c(C)nn2C
Temperature: 25 °C
Yield: 60 %

Procedure:
To a stirred solution of [6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (0.50 g, 0.880 mmol) in ethanol (15 mL) were added H2O2 (1.5 mL) and a saturated aqueous solution of KOH (0.70 g, 11.97 mmol) at 0° C. This mixture was slowly heated to reflux. After 2 h the reaction mixture was cooled to RT, water (10 mL) was added, and the product was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over sodium sulfate and evaporated to yield the crude residue. The crude was purified by column chromatography over 100-200 mesh silica gel using 10% ethyl acetate and petroleum ether to yield the title compound as a sticky oil (yield: 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cncc(Br)c1

Procedure:
To a cooled (0° C.) solution of (5-bromopyridin-3-yl)methanol (38.8 g, 0.206 mol) in dichloromethane (0.6 L) was added a solution of thionyl chloride (149 mL, 2.05 mol) in dichloromethane (200 mL). The resulting mixture was stirred at reflux overnight. The reaction was then concentrated under reduced pressure, and the resulting residue was recrystallized from diethyl ether to provide the title compound: LCMS m/z 206 [M+H]+; 1H NMR (300 MHz, d6-DMSO) δ 12.66 (s, 1H), 8.69-8.74 (m, 2H), 8.25 (s, 1H), 4.83 (s, 2H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]#[N:26])=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: N=C(NO)c1ccccc1
Reactant: N#CCc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Product: N#CCc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4nc(-c5ccccc5)no4)CC3)cn2)cc1

Procedure:
The title compound is prepared from 2-(4-cyanomethyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-benzamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=2.05 min; Mass spectrum (ESI+): m/z=506 [M+H]+.