Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[C:11]3[CH2:22][CH2:21][CH2:20][C:12]=3[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc2c3c(c(OCC4CC4)nn12)CCC3
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylmethanol (1.78 ml) was initially charged in DMF (25 ml). Subsequently, the mixture was admixed with sodium hydride (541 mg) under argon and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 1.31 g) was dissolved in DMF (20 ml) and 11.25 ml of the alkoxide solution were added in portions at 45° C. over 90 min. Then the mixture was stirred at 45° C. for another hour. After adding a little water, the mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 528 mg of the title compound were obtained. LC-MS rt: 0.63 min [M+H]+: 246.1 (met. b)
Reaction SMILES: [Cl:1]C1C(S(C2C=CC=CC=2)(=O)=O)=CC=C(CCC2C=CC(F)=CC=2F)N=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(=[O:45])=[O:44])=[CH:39][N+:38]=1[O-]>>[Cl:1][CH:36]([C:37]1[CH:42]=[CH:41][C:40]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(=[O:45])=[O:44])=[CH:39][N:38]=1)[CH2:35][C:29]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=1[F:27]
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)nc1Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)[n+]([O-])c1
Product: O=S(=O)(c1ccccc1)c1ccc(C(Cl)Cc2ccc(F)cc2F)nc1

Procedure:
2-chloro-6-[2-(2,4-difluorophenyl)ethyl]-3-(phenylsulfonyl)pyridine and the title compound were prepared from 2-[2-(2,4-difluorophenyl)ethyl]-5-(phenylsulfonyl)pyridine 1-oxide according to the method of Example 29 Step 2, separating the products by dry flash column chromatography using toluene-5% ethyl acetate/toluene. m/z (ES+) 394, 396 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:5]=[CH:6][CH:7]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: O=C1CC(=O)N(c2cccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c2ccc3ccccc3c2N1

Procedure:
By using 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 53, (1), and 2-nitrobenzenesulfonyl chloride, the title compound was obtained in the same manner as that of Example 145.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7](=[O:21])[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[NH:9][CH2:10][CH2:11][CH2:12]O>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7](=[O:21])[CH:8]([NH:9][CH2:10][CH2:11][CH2:12][Cl:3])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: COC(=O)C(NCCCO)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NCCCCl)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a solution of thionyl chloride (8.79 g) in chloroform (20 mL) was added (4-fluoro-phenyl)-(3-hydroxy-propylamino)-acetic acid methyl ester (14.85 g, dissolved in 60 mL of chloroform) dropwise via syringe. The reaction mixture was then stirred for 1.5 hours at 50° C. and the volatiles were subsequently removed in vacuo to give a solid residue which was triturated with diethyl ether (30 mL) to give the desired HCl salt of (3-chloro-propylamino)-(4-fluoro-phenyl)-acetic acid methyl ester (14.88 g, MS (ES+): 260.1 (MH+)) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:10]#[N:11])[N:3]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CN(C)C=O
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]
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(C#N)n1
Temperature: 110 °C

Procedure:
2-Chloro-4,6-dimethylpyrimidine (3.3 g, 0.023 mol) was combined with zinc cyanide (2.7 g, 0.023 mol, 1 eq.) and tetrakis(triphenylphosphine)palladium (0) (2.7 g, 0.0023 mol, 0.1 eq.) in DMF (20 ml), and the slurry was heated at 110° C. under nitrogen for 0.5 h. The mixture was cooled to room temperature, diluted with EtOAc (70 ml) and washed twice with 2N ammonium hydroxide (50 ml). The EtOAc solution was washed with brine (20 ml) and concentrated in vacuum to provide the crude mixture. The crude was then purified by column chromatography (30% EtOAc/hexane) to afford 4,6-dimethylpyrimidine-2-carbonitrile. Yield: 0.8 g (26%). 1H NMR (400 MHz, CDCl3): δ2.48 (s, 6H), 7.21 (s, 1H). LCMS: (ES+) m/z=133.6 (M)+
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH:8]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:28](=O)[CH2:29][CH3:30])[C:24](=O)[CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:7])[CH2:5][CH3:6]>C(O)C>[C:4]([CH:8]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[C:28]([CH2:29][CH3:30])=[N:2][NH:3][C:24]=2[CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:7])[CH2:5][CH3:6]
Reactant: CCC(=O)C(CCCOc1ccc(OCCCC(C(=O)CC)C(=O)CC)cc1)C(=O)CC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCC(=O)C(CCCOc1ccc(OCCCc2c(CC)n[nH]c2CC)cc1)C(=O)CC
Reaction time: 8 h

Procedure:
A solution of 0.36 ml (0.00815 m) of hydrazine hydrate in 350 ml of ethanol was added dropwise during a 90 minute period to a solution of 3.3 g (0.0074 m) of 1,4-bis(4,4-dipropionylbutyloxy)benzene in 700 ml of ethanol held at 0°-5° C. and with vigorous stirring. The reaction mixture was then heated at reflux for 2.5 hours and allowed to stand at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was treated with ethereal hydrogen chloride. The solid product which formed was collected and stirred for two hours with 250 ml boiling isopropyl acetate, then filtered and concentrated. The solid residue was recrystallized from isopropyl acetate to give 1.6 g of 4-{3-[4-(4,4-dipropionylbutyloxy)phenoxy]propyl}-3,5-diethyl-1H-pyrazole, m.p. 135°-136° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1.C([NH:35][S:36](Cl)(=[O:38])=[O:37])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][N:25]([S:36]([NH2:35])(=[O:38])=[O:37])[CH2:26][CH:27]=4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: Clc1cccc(Nc2ncc(-c3ccc(C4=CCNCC4)cc3)o2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1

Procedure:
The title compound is prepared from (3-chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-amine bis HCl salt in analogous fashion using N-Boc chlorosulfonamide followed by TFA-mediated deprotection: 1H NMR (400 MHz, DMSO-d6) δ 2.55 (br. s., 2H) 3.15 (t, J=5.56 Hz, 2H) 3.65 (d, J=2.78 Hz, 2H) 6.22 (t, J=3.28 Hz, 1H) 6.92 (dd, J=7.83, 1.52 Hz, 1H) 7.26 (t, J=8.08 Hz, 1H) 7.39-7.53 (m, 7H) 7.79 (t, J=2.02 Hz, 1H); (M+H)+431.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]#[CH:12].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][SH:18].[Na]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]\[CH:11]([S:18][CH:17](/[CH:12]=[CH:11]\[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: C#Cc1ccc(OC)cc1OC
Reactant: COc1ccc(CS)c(OC)c1
Agent: [Na]
Product: COc1ccc(/C=C\C(SC(/C=C\c2ccc(OC)cc2OC)c2ccc(OC)cc2OC)c2ccc(OC)cc2OC)c(OC)c1

Procedure:
A solution of 2,4-dimethoxyphenylacetylene (0.02 mol), 2,4-dimethoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethoxystyryl-2,4-dimethoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([CH2:33][O:34][CH3:35])[CH:30]=[C:29]([F:36])[C:28]=1[C:37]1[N:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[CH:39][C:38]=1[F:46]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:43](=[O:44])[C:41]2[CH:40]=[CH:39][C:38]([F:46])=[C:37]([C:28]3[C:29]([F:36])=[CH:30][C:31]([CH2:33][O:34][CH3:35])=[CH:32][C:27]=3[F:26])[N:42]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(methoxymethyl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 199. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.29 (dd, J=8.6, 4.0 Hz, 1H), 8.15 (t, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.24 (d, J=9.0 Hz, 2H), 4.81 (dd, J=10.3, 3.7 Hz, 1H), 4.53 (s, 2H), 4.31-4.07 (m, 1H), 4.02-3.83 (m, 2H), 3.75 (s, 3H), 3.36 (s, 3H), 3.11-2.98 (m, 1H), 2.10-2.00 (m, 1H), 1.82-1.57 (m, 3H). LCMS (ES+) m/z 508 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[N:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[N:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([C:4]3[CH:13]=[CH:12][C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=3)=[O:3])=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(N2CCOCC2)cc1)c1ccc2c(c1)CCCC2

Procedure:
A solution of 1.74 g of 1 (10 mmoles), 1.91 g of p-(4-morpholinyl)benzaldehyde (10 mmoles), and two pellets of sodium hydroxide (about 0.4 g) in 40 ml of ethanol was stirred under nitrogen at room temperature for 70 hr. The reaction mixture was cooled in an ice bath and the precipitated yellow solid 3-[4-(4-morpholinyl)phenyl]-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-one was collected by filtration and washed with cold ethanol. Yield: 2.9 g (83%); m.p. 138° to 140°. λmax (EtOH): 390 nm (ε=28,100), 270 nm (ε=13,700). Calcd for C23H25NO2 : c, 79.51; H, 7.25; N, 4.03. Found: C, 78.72, 79.02, 78.75; H, 7.22, 7.26, 7.23; N, 3.88, 3.87, 3.91.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:27][CH3:28])[C:8]1[CH:26]=[CH:25][C:11]([NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17]CC)=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:27][CH3:28])[C:8]1[CH:9]=[C:10]2[C:11](=[CH:25][CH:26]=1)[N:12]=[CH:13][C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]2[OH:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(N(CC)CCOC(C)=O)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1cnc2ccc(N(CC)CCOC(C)=O)cc2c1O
Yield: 35 %

Procedure:
To a flask containing crude diethyl 2-({4-[[2-(acetyloxy)ethyl](ethyl)amino]-anilino}methylene)malonate (2.2 g) is added diphenyl ether (15 mL). The reaction mixture is heated from room temperature to 260° C. over 45 minutes under a flow of argon gas. After 1 hour at 260° C. the hot reaction is slowly and carefully added to stirred diethyl ether (150 mL). The resulting precipitate is filtered and washed repeatedly with heptane. The residue is adsorbed onto silica and chromatographed on silica eluting with 3% to 10% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.68 g of ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinolinecarboxylate as a brown solid.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.O>O1CCOCC1>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1

Procedure:
At room temperature, 31.60 g (281.48 mmol) of potassium tert-butoxide and 52.70 g (270.22 mmol) of tert-butyl bromoacetate are added to a solution of 27.50 g (225.18 mmol) of 4-hydroxybenzaldehyde in 200 ml of dioxane, and the mixture is heated at the boil overnight. 1 l of water is added, and the mixture is then extracted with diethyl ether, washed with 1 N sodium hydroxide solution, water and saturated sodium chloride solution and dried over magnesium sulphate, and the solvent is distilled off. Flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) gives, after recrystallization from pentane, the target compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[N:15].[H][H]>[Co].C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CC#N
Agent: [Co]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCN
Yield: 125.8 %

Procedure:
6.00 g (30 mmol) of (5-Methyl-2-phenyl-oxazol-4-yl)-acetonitrile were hydrogenated in the presence of 0.60 g of wet Raney Cobalt catalyst (Blackwell-Catalloy, Type Nr. 1708042) in 54 mL of ethanol in a 185 mL stainless steel autoclave under 9 bar of hydrogen pressure at 70° C. for 3 h. Removal of the catalyst by filtration, evaporation of the solvents and work-up as in example 1 afforded 7.63 g of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamine as its mesylate salt with a purity of 100% (HPLC area %).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.O>C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Solvent: O
Solvent: ClCCl
Product: COc1cccc(Nc2nc(-c3cn[nH]c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with pyrazole-4-boronic acid pinacol ester using General Procedure A. Addition of water and CH2Cl2 to the reaction, followed by sonication and filtration yielded 101. NMR: (CDCl3): 3.87 (s, 3H, CH3), 4.07 (s, 3H, CH3), 6.87 (dd, H, ArH, J=2.4, 8.37), 7.13 (d, H, ArH, J=7.85), 7.29 (m, H, ArH), 7.37 (t, H, ArH, J=8.13), 7.43 (s, H, ArH), 8.37 (s, 2H, 2×ArH). MS: (ESI+) MH+==322.23
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[C:7]2[S:8](=[O:25])[CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cccc(Cl)c1SCC2
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cccc(Cl)c1S(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 0.9 g of 8-chloro-2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, prepared in Example 24, in 20 ml of acetic acid is added 0.6 ml of 35% hydrogen peroxide with stirring at room temperature and the mixture is stirred for 18 hours at the same temperature. To the residue is added water, and the precipitated crystals are collected by filtration and repeatedly washed with ethanol to give 0.7 g of 8-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide, melting at 217°-219° C. with decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)#[N:2].[NH:12]1[C:19](=[O:20])[CH2:18][C:16](=O)[NH:15][C:13]1=[S:14].CS(O)(=O)=O>C(O)CCC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:16]3[NH:15][C:13](=[S:14])[NH:12][C:19](=[O:20])[C:18]=3[CH2:8][C:7]=2[CH:10]=1)#[N:2]
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: N#Cc1ccc(O)c(C=O)c1
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: N#Cc1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
To n-butanol (100 ml.) add 5-cyano-salicylaldehyde (6 g.), 2-thiobarbituric acid (6 g.) and methanesulfonic acid (10 ml.) With stirring, heat the mixture to reflux for 11/2 hours. Cool, filter, and wash the solid with isopropanol and ether to yield 7-cyano-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:23])[CH:8]=2)[N:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(O)ccc2n1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(OCc3ccc(S(C)(=O)=O)cc3)ccc2n1

Procedure:
2-Methyl-4-(3-phenylpyrrolidin-1-yl)quinolin-6-ol (0.05 g; see Example 42 below), 1-bromomethyl-4-methanesulfonylbenzene (0.08 g), caesium carbonate (0.1 g) in DMF (2 mL) was heated in a microwave at 120° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to give an oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. Evaporation of the desired fractions gave the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(C2CCNCC2)c1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.49 g, 2.35 mmol) in DMF (10 mL) is added triethylamine (0.65 mL, 4.7 mmol), followed by 1-hydroxy-7-benzotriazole (0.32 g, 2.35 mmol) and 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol). After stirring 15 min at RT, 3-Piperidin-4-yl-phenylamine hydrochloride (0.50 g, 2.35 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1-[4-(3-amino-phenyl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone as a crude mixture of good enough purity for the next step (0.86 g, quantitative). 1H-NMR (400 MHz, MeOD): δ=1.52-1.63 (m, 1H), 1.64-1.73 (m, 1H), 1.80-1.93 (m, 2H), 2.33 (s, 3H), 2.68-2.81 (m, 2H), 2.99 (s, 2H), 3.21-3.27 (m, 1H), 4.02-4.09 (m, 1H), 4.55-4.62 (m, 1H), 5.12-5.28 (q, 2H), 6.41 (s, 1H), 6.55-6.60 (m, 1H), 6.61-6.62 (m, 1H), 7.00-7.07 (t, 1H), 7.99 (s, 1H). MS: m/z=367 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=2)[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl[C:36]([C:38]1[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=1)[CH2:41][S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[O:37]>O1CCCC1>[CH3:28][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:3]3[CH:4]=[C:5]([N:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:6]=[CH:7][C:2]=3[NH:1][C:36]([C:38]3[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=3)[CH2:41][S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[O:37])[CH:19]=2)[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3N)c2)cc1C
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(Nc3ccc(C)c(C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of 2-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3,4-dimethylphenyl)pyridin-4-amine (270 mg, 0.72 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), pyridine (170 mg, 2.15 mmol, 2.97 equiv), and methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (197.6 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. This reaction was used directly in next step without workup.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([CH:11]=O)[N:10]=[C:4]2[N:3]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[C:21]([CH2:11][C:9]3[N:10]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]4[N:8]=3)=[C:20]([OH:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccn2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)ccn4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(224) where 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30-1.80 (brm, 8H), 2.00-2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.68 (s, 1H), 2.70(s, 2H); 2.92 (m, 2H), 3.69 (m, 3H), 6.64 (d, J=3.56 Hz, 1H), 6.66 (d, J=3.56 Hz, 1H), 7.00 (m, 2H), 8.55 (d, J=6.97 Hz, 1H). Anal. Calcd. For C27H32O4N4: C, 68.05; H, 6.77; N, 11.76. Found: C, 68.24; H, 6.80; N, 11.77.