Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCN(c2ccccc2OC)CC1
Yield: 68.4 %

Procedure:
A stirred mixture of 1-(2-methoxyphenyl)piperazine (1.50 g, 7.8 mmol), ethyl 4-bromobutanoate (0.9 mL, 6.3 mmol), and K2CO3 (0.87 g, 6.3 mmol) in acetonitrile was refluxed overnight. After the mixture was cooled, the mixture was evaporated to dryness and H2O (20 mL) was added to the residue. The aqueous phase was extracted with CH2Cl2 (230 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 1:1, as eluent) to afford pure 13 as a pale yellow oil (1.32 g, 68% yield). 1H NMR: δ 1.24 (t, 3H, J=7.1 Hz, CH2CH3), 1.79-1.89 (m, 2H, CH2CH2CO), 2.34 (t, 2H, J=7.3 Hz, COCH2), 2.41 [t, 2H, J=7.4 Hz, (CH2)2NCH2], 2.63 [br s, 4H, (CH2)2NCH2], 3.06 [br s, 4H, ArN(CH2)2], 3.83 (s, 3H, OCH3), 4.11 (q, 2H, J=7.1 Hz, CH2CH3), 6.82-7.00 (m, 3H, aromatic). GC-MS m/z 307 (M++1, 18), 306 (M+, 77), 261 (32), 205 (100), 190 (37).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-[3-chloro-4-(napthalen-2-ylsulfanyl)-phenyl]-benzene sulfonamide was synthesized (67%) from 3-chloro-4-(napthalen-2-ylsulfanyl)phenylamine (92) and 2,4-dichlorobenzenesulfonyl chloride, obtained from Maybridge, in a similar manner as described in example 93.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)cc2)c1
Yield: 91.3 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-1-sulfonyl)-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (196 mg, 0.28 mmol) and 1.0 N aqueous sodium hydroxide (2.8 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-(propane-1-sulfonyl)-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (165 mg, 92%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C34H41ClO8S (M+Na)+ 667.2103, found 667.2102.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[F:26][C:27]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:25][C:4]1[N:3]=[C:2]([C:33]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of crude 4-chloro-6-[2-(4-phenyl-1H-imidazol-2-yl)-4-morpholinyl]-2-pyrimidinamine, 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (765 mg, 3.10 mmol), Na2CO3 (631 mg, 5.96 mmol) and Pd(PPh3)4 (275 mg, 0.238 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1.0 hour. The mixture was filtered, washed by EtOAc (150 mL), and concentrated to afford the crude title compound (1.3 g) as a yellow solid. This material was combined with another batch of crude title compound (100 mg). The combined material was washed by EtOAc (150 mL), and concentrated. The resulting residue was purified by silica gel chromatography using EtOAc in petroleum ether from 50% to 70% to afford the title compound (400 mg) as a light yellow solid. LC-MS (ES) m/z=442 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[CH3:15][N:16]1[CH:20]2[CH2:21][C:22]([CH2:24][CH:17]1[CH2:18][CH2:19]2)=[O:23].[OH-].[Na+]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:23])[CH2:21][CH:20]3[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]3)[CH2:24]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
To 4.0 mL (7.04 g, 31.18 mmol) 4-bromo-1,2-dichloro-benzene in 100 mL THF at −78° C. is added 12.47 mL of a 2.5 M solution of n-BuLi in hexanes in drops over 5 min. After stirring at −78° C. for 45 min, 4.34 g (31.18 mmol) tropinone is added as a solid. The resulting mixture is warmed to 23° C. and stirred for 18 h. After pouring into 2.5 N NaOH, the reaction mixture is extracted with 2×100 mL EtOAc, the organics are combined and washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and evaporated to an off-white solid. Flash chromatography on SiO2 gel, eluting with CHCl3/MeOH (20/1 to 5/1), gives 2.58 g (9.02 mmol, a 28% yield) of the title compound as a white solid. mp: 153-154° C.; MS (ES) m/z 287 (MH)+.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Na+].[I-].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:31][CH2:30]1
Reactant: O=C1CCc2ccc(OC/C=C/CCl)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1CCc2ccc(OC/C=C/CN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of intermediate 52 (75 mg, 0.25 mmol) and NaI (75 mg, 0.5 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 41 (102 mg, 0.38 mmol) and anhydrous K2CO3 (138 mg, 1 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give (E)-7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyloxy)-3,4-dihydroquinolin-2(1H)-one (compound 29) (79 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.77 (s, 1H), 7.16-7.14 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.98-6.94 (m, 1H), 6.53 (d, J=8.1 Hz, 1H), 6.33 (s, 1H), 5.94-5.89 (m, 2H), 4.51 (d, J=4.2 Hz, 2H), 3.19-3.08 (m, 6H), 2.90 (t, J=6.9 Hz, 2H), 2.67-2.59 (m, 6H). HPLC: 99%, RT 2.468 min. MS (ESI) m/z 446.1 [M+H]+. mp: 151-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@H:31]([N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]1=[O:22])[CH2:32]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CN2CCC1CC2

Procedure:
(5Z)-3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane following General Procedure J.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19]C)=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A 500-mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alaninate (8.81 g, 30.7 mmol), 100 mL of THF, 100 mL of water and lithium hydroxide (2.20 g, 92 mmol). After stirring overnight at room temperature, the mixture was concentrated and acidified to pH 3 with concentrated aqueous HCl. The mixture was then extracted with EtOAc, dried (MgSO4), filtered, and concentrated to give N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (8.00 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][O:11][C:12]=1[CH3:13])=[O:7].Br.Br.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:35])=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:35])=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])=[O:7])[CH2:33][CH2:34]2)[CH:28]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCCCCl
Reactant: Oc1ccc(Cl)cc1N1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCN(c2cc(Cl)ccc2O)CC1
Temperature: 160 °C
Yield: 125.4 %

Procedure:
A mixture of 0.28 g of Compound 2B, 0.21 g of Compound 2A and 0.14 g of potassium carbonate was heated at 160° C. for 20 minutes. After cooling to room temperature, the mixture was taken up with 8 mL of chloroform, and inorganic matter was filtered off. The filtrate was evaporated to dryness and purified by flash chromatography (chloroform:methanol 97.5:2.5) to yield 0.32 g (71%) of the title compound. M.p. 92-98° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:34][O:35][C:36]([C:38]1([NH2:46])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37]>O1CCCC1>[CH3:34][O:35][C:36]([C:38]1([NH:46][C:9](=[O:11])[CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=2[CH3:12])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37]
Reactant: Cc1cc(F)c(Br)cc1CC(=O)O
Reactant: COC(=O)C1(N)CCN(OC)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)Cc2cc(Br)c(F)cc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid (8.0 g) and 1,1′-carbonyldiimidazole (5.8 g) in tetrahydrofuran (150 ml) is heated at reflux for 30 minutes. Upon cooling to room temperature, triethylamine (9.0 ml) and 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride salt (13.8 g) are added and warming at reflux is continued for 3 hours. The cold reaction mixture is poured on water/ethyl acetate, the layers separated, the organic phase washed with brine, dried over sodium sulfate and concentrated. The residue is solubilised in ethyl acetate/cyclohexane 3:1 and purified by filtration on alumina. Yield: 6.83 g of 4-[2-(5-bromo-4-fluoro-2-methyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester as a solid, mp: 192-193° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].Br[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1)=[O:23].O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22]([CH2:21][N:6]2[C:7]3[C:12](=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:2])=[O:4])=[O:23])=[N:26][CH:27]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)O)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 2 h

Procedure:
To a solution of 1 g 5-Methanesulfonyl-1H-indole-2-carboxylic acid methyl ester in 10 ml DMF, 158 mg (60% in oil) sodium hydride were added at RT. After stirring for 10 min 985 mg 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture was stirred for 2 h. After the addition of 7 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and concentrated under reduced pressure. The residue was taken-up in 10 ml water/THF 1:2 and treated with 2 ml aqueous KOH solution (10%). After stirring for 16 h at RT the reaction mixture was acidified with hydrochloric acid (5M). The precipitate was collected by filtration and dried in vacuo to yield the product as a yellow solid. Yield: 1.1 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([CH3:14])[C:9](OCC)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH:8]([CH3:14])[CH2:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1ncccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1ncccc1Cl
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a −15° C. solution of the product of Example 38B (1.34 g, 6.27 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (0.238 g, 6.27 mmol). The reaction mixture was kept between −5° C. and −15° C. for 1 hour and then quenched by the addition of solid sodium sulfate decahydrate. The quenched reaction mixture was filtered through a pad of celite with ethyl acetate and the filtrate concentrated. The residue was chromatographed on silica gel with 35% ethyl acetate-hexane to give the title compound (0.90 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (dd, J=1.5, 4.6, 1H), 7.85 (dd, J=1.6, 8.1, 1H), 7.26 (dd, J=4.6, 8.1, 1H), 4.70-4.55 (m, 1H), 3.82-3.62 (m, 1H), 3.59-3.39 (m, 2H), 1.16 (d, J=6.5, 3H). MS (DCI) m/z 172 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.CO>O=[Pt]=O.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Yield: 80.4 %

Procedure:
To a solution of 40 g of N-(3-nitro-4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide in 900 ml. of MeOH and 100 ml. of EtOAc in a hydrogenation bottle is added 0.5 g PtO2. The bottle is purged with hydrogen then pressurized to 50 psig and shaken until the required amount of H2 was used. The reaction mixture was filtered through celite, washed well with CH2Cl2 and the combined organic phases concentrated in vacuo to yield 29 g of the product. This product was used without further purification in subsequent transformations.
Reaction SMILES: CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C[N:17]([CH2:25][C@H:26]1[CH2:29][C@H:28]([O:30]C2C=CC(CN3CCCC3)=CC=2)[CH2:27]1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].NC[C@@H]1C[C@H](O)C1.CCN(CC)CC>C1COCC1>[OH:30][C@@H:28]1[CH2:29][C@H:26]([CH2:25][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:27]1
Reactant: CN(C[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O)C1

Procedure:
(Boc)2O (4.42 g, 0.02 mol) was added to a solution of intermediate 9, cis-3-(aminomethyl)cyclobutanol (1.95 g, 0.019 mol) and Et3N (5.6 mL, 0.039 mol) in 20 mL absolute THF under stirring. The mixture was stirred at room temperature for 30 min, evaporated, and coevaporated with CCl4. The residue was recrystallized form ether to give the title compound (3 g, 77%) as yellow crystals. 1H NMR-data (DMSO-d6): 6.61-6.87 (m, 1H, NH); 4.85 (br.s, 1H, OH); 3.77-3.92 (m, 1H); 2.90 (t, 2H, CH2, J=6.1 Hz); 2.10-2.22 (m, 2H); 1.67-1.80 (m, 1H); 1.21-1.51 (m, 11H, CH2, Boc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.C(O)(=[O:27])C.C(N(C(C)C)CC)(C)C.O>CN1CCCCC1=O>[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2](=[O:27])[NH:3][N:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Agent: CN1CCCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 7 h

Procedure:
1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (1.0 g) prepared in Example 1 was dissolved in 10 ml of N-methyl-2-piperidone, followed by the addition of 0.26 ml of acetic acid and 2.1 ml of diisopropylethylamine. The obtained mixture was stirred at 170° C. for 7 hours, followed by the addition of 100 ml of water. The crystals thus precipitated were recovered by filtration.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: CC(C)(C=O)Cc1ccccc1
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(C)(CO)Cc1ccccc1
Yield: 89.3 %

Procedure:
354 g 2,2-dimethyl-3-phenyl-propanal (1a) was hydrogenated in an autoclave with 2 g copper chromite (G-79) at 150° C. and 120 bar until it had absorbed 1 equivalent of hydrogen. When the pressure had been released in the autoclave the catalyst was separated off. Distillation on a 60 cm packed column yielded 320 g (90%) 2,2-dimethyl-3-phenyl-propanal (1b) in the form of a colourless, viscous oil. bp (2 mm)=90° C., mp. 34°-36° C. --NMR (CCl4): δ-0.88, s, 6H (2,2--CH3), 2.55, s (CH2 --3), 3.37, s (CH2 --1), 7.1-7.3, br.s (phenyl--H). --IR: 3400 cm-1 (O--H). --MS: m/e (%)=164 (16, M+), 133 (5), 131 (4), 117 (6), 115 (8), 105 (4), 92 (100), 91 (83). C11H16O (164.2).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])[CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.Br[CH2:22][CH:23]=[CH2:24]>CN(C)C=O>[CH2:12]([C:11]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH2:24][CH:23]=[CH2:22])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)=[O:20])[CH3:13]
Reactant: C=CCBr
Reactant: CCC(C(=O)c1ccc(F)cc1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(CC)(C(=O)c1ccc(F)cc1)N1CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
56 g of a 50% suspension of sodium hydride in mineral oil (0.22 mol sodium hydride) is added to 100 ml dimethylformamide. 45.2 g (0.16 mol) 1-(4-Fluorophenyl)-2-(morpholin-4-yl)-1-butanone, dissolved in 50 ml diemethylformamide, are added to this suspension dropwise and at room temperature, and subsequently stirred overnight. Then, 19.36 g 1-brom-2-propene are added dropwise. The temperature raises to 50° C. and the solution is kept at this temperature for 16 hours. After cooling, excess sodium hydride is destroyed by the addition of 5 ml isopropanol and the reaction mixture subsequently poured onto an ice/water mixture. The organic products are extracted with ethyl acetate, the combined extracts dried over magnesium sulfate and the solvent evaporated. The crude product thus obtained is purified by chromatography silica gel (eluent: ethyl acetate/petroleum ether 4:1). 2-Ethyl-1-(4-fluoro-phenyl)-2-(morpholin-4-yl)-pent-4-en-1-one (17.8 g, 38%) is obtained as a yellowish oil. 1H-NMR analysis is in agreement with the proposed structure. This compound is used for the next step.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:8]=[N:9]O)=[C:5]([Cl:7])[N:6]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[S:3][C:4]([C:8]#[N:9])=[C:5]([Cl:7])[N:6]=1
Reactant: ON=Cc1sc(Cl)nc1Cl
Solvent: CC(=O)OC(C)=O
Product: N#Cc1sc(Cl)nc1Cl
Temperature: 137 °C

Procedure:
400 g (2.03 mol) of crude 2,4,-dichloro-5-thiazolecarboxaldehyde oxime (IV) are stirred with 2 liters of acetic anhydride at reflux temperature (137° C.) for 4 hours. Fractionation using a silvered distillation column 1 m long provided 271 g (=75.7% of theory) of 2,4-dichloro-5-thiazolecarbonitrile (V) at 112° C./20 m bar, this product being identical by mass and IR spectroscopy with that described in German Offenlegungsschrift No. 3,038,608 (which can also be named 2,4-dichloro-5-cyanothiazole). The compound solidifies at room temperature to give colourless crystals which can be recrystallized from petroleum ether. Melting point: 34°-35° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 72.4 %

Procedure:
To a mixture of 4-nitrophenol (100 g, 719 mmol) and anhydrous K2CO3 (400 gm, 2.894 mol) in anhydrous acetone (950 ml) was added methyl chloroacetate (114 g, 1.050 moles) and refluxed for 12 hours. Acetone was distilled off and water (1500 ml) was added. Crude 7 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 7 (110 g, 72.5%) as a white fluffy powder with an m.p between 97-98.4° C.