Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][C:33](=[O:35])[C:32](=[CH:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[S:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:40]3[CH:39]=[CH:38][C:37](/[CH:36]=[C:32]4/[C:33](=[O:35])[NH:34][C:30](=[O:29])[S:31]/4)=[CH:44][CH:43]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)/C(=C/c2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)S1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 594.1.
Reaction SMILES: [CH3:1]I.[Li+].[BH4-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:20][CH3:21])[C:16]=1[CH:17]([CH3:19])[CH3:18])[C:10]([O:12]C)=O.Cl>CCOCC.O>[CH3:21][O:20][C:15]1[CH:14]=[C:9]([CH:10]([OH:12])[CH3:1])[CH:8]=[C:7]([O:6][CH3:5])[C:16]=1[CH:17]([CH3:19])[CH3:18]
Reactant: CI
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(C(C)O)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of Mg (2 g, 82.2 mmol) in dry ether (100 mL) was added CH3I (5 mL, 80.4 mmol) in dry ether (100 mL). After the addition was completed, the reaction mixture was refluxed for 1 hour and then cooled to 0° C. LiBH4 (2.0M in THF, 25 mL, 50 mmol) was added followed by addition of methyl 3,5-dimethoxy-4-i-propylbenzoate (10.0 g, 42.0 mmol) in dry ether (300 mL). The reaction was stirred at 0° C. overnight. Water (50 mL) was added dropwise followed by 2N HCl (100 mL). The organic layer was separated and the aqueous extracted with ether (4×200 mL). The extract was dried over anhydrous sodium sulfate. Evaporation of the solution yielded a liquid mixture. This was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 100 °C

Procedure:
7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100° C. until there is no further reaction and after cooling it is evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11](CCC)=[CH:10][CH:9]=2)[CH2:3]1.BrC1C=C[C:21]([O:24]CCC)=[CH:20][CH:19]=1>>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([O:24][CH2:21][CH2:20][CH3:19])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Reactant: CCCOc1ccc(Br)cc1
Product: CCCOc1ccc(N2CCN[C@H](C)C2)cc1
Yield: 34 %

Procedure:
The title compound was prepared following the procedure of Intermediate 17, but starting from 1-bromo-4-propoxybenzene. Purification by chromatography (DCM/MeOH 80/20) afforded the title compound as a brown oil (34%). HPLC (Condition A), Rt: 1.9 min (HPLC purity: 80.2%). M+(ESI): 235.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>CC(C)=O>[C:28](=[O:29])([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)[O:30][CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)COC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (2.50 g; 0.00783 mole) in acetone (50 ml) at 0° was treated with triethylamine (0.87 g; 0.00861 mole) followed by isobutyl chloroformate (1.17 g; 0.00861 mole) dropwise, during 30 minutes at 0°-2°.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:30]
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2cnn(CCCCC(C)=O)c2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 01: tR=0.85 min; [M+H]+=372.16.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20](F)=[CH:19][CH:18]=[CH:17][C:16]=2F)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccccc1
Product: Cn1c(-c2ccccc2)nc(C(=O)NCc2ccccc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (62 mg, 0.2 mmol) and benzylamine (64 mg, 0.6 mmol). The title product was obtained as a white solid (45 mg, 61% yield). 1HNMR (500 MHz, CDCl3) δ:). 12.38 (1H, s), 7.82 (1H, br s), 7.53–7.47 (1H, m), 7.37–7.29 (5H, m), 7.25–7.26 (2H, m), 7.07–7.04 (2H, m), 4.60 (2H, d, J=5.8 Hz), 3.42 (3H, s). HRMS calcd for C19H16F2N3O3 (M+H): 372.1160; found: 372.1156. Anal. Cald for C19H15F2N3O3: C, 61.45, H, 4.07; N, 11.31; found: C, 61.12, H, 3.77; N, 11.06
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:38]1C=CC(C)=C[C:39]=1S(Cl)(=O)=O>>[CH2:38]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:25])=[O:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:39]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1F

Procedure:
2-Fluoro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}benzoic acid, m/z (ES+): 499.31 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]4[CH2:20][CH2:21][CH2:22][O:23][C:12]=34)=[O:10])[CH2:3][CH2:2]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Reactant: BrCC1CCCCC1
Product: O=C(NCC1CCN(CC2CCCCC2)CC1)c1c2n(c3ccccc13)CCCO2
Reaction time: 8 h

Procedure:
N-(4-Piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21) was alkylated with cyclohexylmethyl bromide using the method of Example 22 with a reaction time of 70 h at room temperature followed by 8 h at reflux temperature. The title compound (E23) was obtained as a white solid (31%) which was converted to its hydrochloride salt and crystallised from acetone/ether as a white solid mp 209-210° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[CH3:36][O:37]CCN>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][CH2:2][O:37][CH3:36])=[O:5]
Reactant: COCCN
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCCOC)C(O)C3O)c2n1

Procedure:
The title compound was prepared according to the method of example 1, step d), using the product of example 1, step c) and 2-methoxyethylamine, followed by deprotection according to the method of example 1, step e).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[C:11]([CH3:14])[NH:12][CH:13]=[C:9]2[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:5]1[C:10]2=[C:11]([CH3:14])[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:13]=[C:9]2[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1[nH]cc2c(=O)n(C)c(=O)n(CC(C)C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A suspension of 1-isobutyl-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (78 mg, 0.33 mmol), 1-(chloromethyl)-4-methoxybenzene (88 μL, 0.63 mmol) and cesium carbonate (344 mg, 1.06 mmol) in anhydrous DMF is stirred at room temperature overnight. The mixture is diluted with 30 mL of water, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is concentrated under vacuum. The residue is purified by basic alumina column chromatography to give 110 mg of product (yield: 93%). MS (ESI) m/z 356.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([O:24][CH3:25])=[N:22][NH:23][C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C(=O)N([Br:33])C(=O)C1.O>CN(C=O)C>[Br:33][C:16]1[C:17]2[NH:23][N:22]=[C:21]([O:24][CH3:25])[C:18]=2[CH:19]=[N:20][C:15]=1[NH:14][C:12]([NH:11][C@@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][O:2][CH3:1])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC[C@@H](NC(=O)Nc1cc2[nH]nc(OC)c2cn1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H](NC(=O)Nc1ncc2c(OC)n[nH]c2c1Br)c1ccccc1

Procedure:
(S)-1-(2-Methoxy-1-phenylethyl)-3-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (Example 41, 53 mg, 0.155 mmol) and NBS (35.5 mg, 0.199 mmol) were stirred in DMF (1 mL) at room temperature for 6 hours. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave (S)-1-(7-bromo-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(2-methoxy-1-phenylethyl)urea MS: [M+H]+ m/z 420. 1H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.08 (d, J=7.0 Hz, 1H), 8.67 (s, 1H), 7.98 (s, 1H), 7.35-7.30 (m, 4H), 7.25-7.21 (m, 1H), 5.03-4.98 (m, 1H), 4.01 (s, 3H), 3.63-3.56 (m, 2H), 3.27 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Yield: 87.6 %

Procedure:
In an argon atmosphere, 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (218 mg) and 65% oily sodium hydride (39 mg) were dissolved in DMF (5 ml) added thereto. With stirring under ice cooling, 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg) was added, followed by stirring at room temperature for 3 hours. After water was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over sodium sulfate, after which it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethanol=24:1), after which it was recrystallized from ethyl acetate to yield the titled compound (368 mg) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[NH:25][N:26]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cccnc1C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2ncccc12

Procedure:
A suspension of 2-[4-(1H-imidazol-1-yl)benzoyl]-3-carbomethoxypyridine (0.94 g, 3.06 mmol) in 50 mL of EtOH is treated with 0.36 g (7.17 mmol) of hydrazine monohydrate. The mixture is heated to reflux for 1 day, then allowed to cool and filtered to give crude product. Crystallization from DMF gives 8-[4-(1H-imidazol-1-yl)phenyl]-5-oxo-5,6-dihydropyrido[3,2-d]-pyridazine as white crystals. M.P. 376°-378° C.
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][N:5]1[CH3:17])[CH3:3].Cl.C(O)(C)C>CO>[ClH:1].[ClH:1].[NH2:14][C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH:4]([CH2:2][CH3:3])[N:5]([CH3:17])[CH2:6]2)=[CH:11][CH:10]=1
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2CN1C
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CCC1Cc2ccc(N)cc2CN1C
Reaction time: 1 h
Yield: 192.2 %

Procedure:
To a pressure bottle charged with 3-ethyl-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.6 g, 17 mmols) dissolved in methanol (100 ml) and saturated isopropanol-HCl (20 ml) was added 10% Pd--C (250 mg), and the reaction was hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to give the title compound (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]#[N:16])[N:11]([CH3:17])[N:10]=2)=[C:4]([F:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:27][C:26]#[CH:25])=[CH:6][C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]#[N:16])[N:11]([CH3:17])[N:10]=2)=[C:4]([F:18])[CH:3]=1
Reactant: C#CCBr
Reactant: Cc1c(-c2cc(O)c(Cl)cc2F)nn(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-c2nn(C)c(C#N)c2C)c(F)cc1Cl
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
1.33 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-cyano-1-methyl-[1H]-pyrazole (Example H6) are dissolved in 25 ml of acetone, and 1.38 g of potassium carbonate are added. The reaction mixture is stirred for 10 minutes at 22° C., and 0.89 g (0.56 ml) of propargyl bromide is then added dropwise with stirring, and stirring is continued for 5 hours at this temperature. The solvent is subsequently distilled off in vacuo and the residue is taken up in diethyl ether. After the etheric solution has been washed with water and saline and the solvent evaporated off, the desired product is obtained in a yield of 1.36 g (89.9% of theory).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:12])[CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Clc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)c1ccc(Cl)cc1

Procedure:
2-[2-(4-Chlorophenyl)-2-oxoethyl]-benzoic acid (above) was prepared by method I using homophthalic anhydride and chlorobenzene. In this case, it was found to be advantageous to heat the reaction to 85° C. for 4 hours. The product was isolated by flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]=[C:14]=[O:15]>C1(C)C=CC=CC=1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:15]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of methyl 4-aminobenzoate (15 g, 99 mmol), and methyl isocyanate(11.8 mL, 200 mmol) in toluene (400 mL) was heated at 100° C. under N2 for 3 hours during which time a precipitate formed slowly. Additional methyl isocyanate (11.8 mL, 200 mmol) was added and heating wascontinued for 2 hours. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with ether and vacuum-dried to give methyl 4-(N-methylaminocarbonyl)aminobenzoate as a colorless solid (17.5 g, 85% ).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7].[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([CH2:25][CH2:26][CH2:27][N:10]1[CH2:11][CH2:12][CH:8]([C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNC1
Reactant: BrCCCOc1ccccc1
Product: O=C(c1cccc(C(F)(F)F)c1)C1CCN(CCCOc2ccccc2)C1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 3-(3-trifluoromethylbenzoyl)pyrroldine (U.S. Pat. No. 3,489,769) and 3-phenoxypropyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([Cl:23])=[O:20])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2nc3ccc(C(=O)O)cc3s2)cn1
Product: COc1ccc(-c2nc3ccc(C(=O)Cl)cc3s2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-Methoxypyridin-3-yl)-1,3-benzothiazole-6-carboxylic acid (40 mg, 0.14 mmol) was mixed with thionyl chloride (1 mL) and stirred at r.t. for 3 h, then heated to 50° C. for 1 h. The solvent was evaporated in vacuo to give the intermediate, 2-(6-methoxypyridin-3-yl)-1,3-benzothiazole-6-carbonyl chloride as a crude product. This acid chloride was dissolved in DCM (3 mL) and added to pyrrolidine (0.5 mL) in CH2Cl2 (1.5 mL). The reaction was stirred at r.t. for 1 h. Water was added and the reaction mixture was extracted, twice, with DCM, dried (MgSO4), filtered and the solvent was evaporated. The solid was dried (in vacuo over P2O5) to give the title compound (45 mg) as an off-white solid. 1H NMR δ 8.92 (d, 1H) 8.39 (dd, 1H) 8.35 (s, 1H) 8.07 (d, 1H) 7.67 (d, 1H) 7.04 (d, 1H) 3.97 (s, 3H) 3.51 (t, 2H) 3.45 (t, 2H) 1.78-1.95 (m, 4H); MS m/z (M+H) 340.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].CO.C[O-].[Na+]>>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: COC(CBr)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(SCC(OC)OC)cc1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, 4-methoxybenzenethiol (3.07 ml, 25.0 mmol) and 2-bromo-1,1-dimethoxyethane (3.25 ml, 27.5 mmol) were added to a sodium methoxide methanol solution (0.5 M, 80.0 ml, 40.0 mmol) under cooling with ice. The reaction mixture was stirred at the same temperature for 10 minutes, and then heated to reflux for five hours. The reaction mixture was concentrated under reduced pressure and cold water was added. The resulting mixture was extracted with ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (5.30 g, 93%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:37])(=[N:27][C:28](=[O:36])[NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:26])=[CH:21][CH:20]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:37])=[O:26])=[O:36])[CH:31]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CS(=O)(=NC(=O)Nc1cccnc1)c1ccc(N)cc1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3cccnc3)cc2)ncc1-c1cccs1
Yield: 4 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (30.7 mg, 0.11 mmol) with (RS)—S-(4-aminophenyl)-N-(pyridin-3-ylcarbamoyl)-S-methylsulphoximide (30 mg, 0.1 mmol) according to procedure 5c, the desired product is obtained in 4% yield (2.3 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol) and HPLC).