Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:23]=[CH:24][C:18]=3[N:17]=2)=[C:11]([Cl:37])[CH:10]=1)(C)(C)C.Cl>C1(OC)C=CC=CC=1.O1CCOCC1>[Cl:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])[CH:10]=[C:11]([Cl:37])[C:12]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]3[O:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[N:28][N:29]=3)[CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Product: O=C(O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 100 ml rbf was added 0.090 g (0.157 mmol) of 3-(3,5-Dichloro-4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-phenyl)-propionic acid tert-butyl ester, a few drops of anisole, and 3 mL 4M HCl in 1,4-dioxane. The purple solution was allowed to stir at r.t. for 72 h. The reaction mixture was concentrated and the residue purified by basic HPLC (ACN/0.005 mM H2O—NH4OH, 2.5:7.5 to 8:2) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (t, J=7.45 Hz, 2H) 3.07 (t, J=7.33 Hz, 2H) 7.75 (s, 2H) 7.84-7.89 (m, 2H) 7.99 (d, J=7.45 Hz, 1H) 8.20 (dd, J=8.46, 1.39 Hz, 1H) 8.32-8.37 (m, 2H) 8.56 (br. s., 1H). MS (m/z) 515.0 M (+1), tR=1.19, Meth 10
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([NH:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[NH:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:35]2[CH:34]=[C:33]([NH:41][S:42]([C:45]3[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[C:32]([NH:31][CH2:29][CH3:30])=[N:37][CH:36]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CCNc1ncc(B(O)O)cc1NS(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 45 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (25 mg, 0.06 mmol) was treated with 6-(ethylamino)-5-(4-methoxyphenylsulfonamido)pyridin-3-ylboronic acid (30 mg, 0.09 mmol), 2M cesium carbonate (60 μl, 0.12 mmol) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3 mg, 0.01 mmol) according to the method described in Example 3 to give 18 mg (48% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)C.[OH-].[K+].CO.O>CO>[S:11]1[C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2
Reactant: CCOC(=O)CCc1cc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To a solution of benzo[b]thiophene-2-propanoic acid ethyl ester (3.52 g, 15.0 mmol) in MeOH (200 mL) was added at 0° C. 10% KOH/MeOH (70 mL, 144 mmol) and H2O (30 mL). The solution was stirred at 25° C. for 6 h then kept in a refrigerator (0° C.) overnight. After addition of H2O (20 mL), the mixture was concentrated under reduced pressure to remove most of MeOH then acidified carefully with 3N HCl to pH 2. The resultant turbid mixture was extracted with Et2O (3×500 mL). The combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated to dryness to give benzo[b]thiophene-2-propanoic acid (3.04 g, 14.7 mmol) in 98% yield as a solid, mp 140°-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[NH:11])OCC)=[O:5])[CH3:2].[ClH:12].[CH3:13][NH:14][CH3:15]>C(O)C>[ClH:12].[CH3:13][N:14]([CH3:15])[C:7](=[NH:11])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)N(C)C

Procedure:
107.3 g (0.67 mol) of the compound from Example 2 and 55 g (0.67 mol) of dimethylamine hydrochloride in 300 ml of ethanol are heated under reflux overnight. The solvent is removed by distillation and the residue is triturated with acetone
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH:22]([NH2:24])[CH3:23])[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[C:15]2[C:31]1[O:32][C:33]([CH3:36])=[N:34][N:35]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:24][CH:22]([C:17]2[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[C:15]([C:31]3[O:32][C:33]([CH3:36])=[N:34][N:35]=3)[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([F:11])[CH:13]=3)[N:18]=2)[CH3:23])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: Cc1nnc(-c2c(-c3ccccn3)c(C(C)N)nc3ccc(F)cc23)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nnc(-c2c(-c3ccccn3)c(C(C)Nc3ncnc(N)c3C#N)nc3ccc(F)cc23)o1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (0.030 g, 0.192 mmol), 1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)-ethanamine (0.067 g, 0.192 mmol), and N,N-diisopropylethylamine (0.167 mL, 0.959 mmol) in 1-butanol (1.918 mL) was stirred at 120° C. After 20 h, the mixture was removed from heat and to the cooled mixture was added water (50 mL) and DCM (50 mL). The organic layer was concentrated in vacuo to give the crude material as a light yellow solid. The light yellow solid was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide 4-amino-6-((1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56-8.62 (1H, m), 8.22-8.29 (1H, m), 7.85-7.93 (3H, m), 7.82 (1H, td, J=7.7, 1.8 Hz), 7.58 (1H, d, J=7.2 Hz), 7.42-7.47 (1H, m), 7.38 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.24 (2H, br. s.), 5.54 (1H, quin, J=6.7 Hz), 2.34 (3H, s), 1.39 (3H, d, J=6.7 Hz); LC-MS (ESI) m/z 468.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1ccc(CNCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 81.8 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-methoxybenzaldehyde (0.78 g) were reacted and treated in the same manner as in Example 121 to give 2.15 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-methoxybenzylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=O)[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].CCOCC>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Reaction time: 18 h
Yield: 32.2 %

Procedure:
Ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (33 g, 73 mmol) and zinc (90 g, 1.38 mol) were refluxed in acetic acid for 66 h. An additional quantity of zinc (25 g, 0.38 mol) was added and reflux continued for 18 h. The mixture was filtered hot and the filtrate was evaporated to a yellow solid. The solid was purified by 800 g Biotage column eluting with 20% ethyl acetate/hexane to give a white solid, which was triturated in ether to give a white solid. A further fraction was obtained by crystallisation from the ether residues. A total of 10.2 g, 32% of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[F-].[K+].[O:22]1[CH2:27][CH2:26]OCC1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:8]1([C:7]2[C:2]([C:8]3[CH:9]=[CH:10][C:26]([CH:27]=[O:22])=[CH:6][CH:7]=3)=[N:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1COCCO1
Reactant: Clc1nc(-c2ccccn2)ncc1-c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Product: O=Cc1ccc(-c2nc(-c3ccccn3)ncc2-c2ccccc2)cc1

Procedure:
4-Chloro-5-phenyl-2-pyridin-2-ylpyrimidine (4-2; 0.15 g, 0.56 mmol), (4-formylphenyl)boronic (0.126 g, 0.840 mmol), bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.028 mmol) and anhydrous KF (0.107 g, 1.85 mmol) were stirred in 2 ml anhydrous dioxane under N2. The reaction was heated to reflux. After 15 min an additional sample of bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.028 mmol) was added and the reaction was heated at reflux overnight. The reaction was cooled and diluted with water. The mixture was extracted 3× with DCM. The combined organic phases was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (dissolved sample in DCM, eluted with 98:2 DCM/EA) and provided an impure sample of 4-(5-phenyl-2-pyridin-2-ylpyrimidin-4-yl)benzaldehyde (4-3) that was used directly in the next transformation.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:18])[CH:13](Cl)[C:14]([CH3:16])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:20]([NH2:23])(=[S:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:13]3[S:22][C:20]([CH3:21])=[N:23][C:14]=3[CH3:16])=[O:18])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(N)=S
Reactant: CC(=O)C(Cl)C(=O)Nc1cccc2c1CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(C(=O)Nc2cccc3c2CCC3(C)C)s1
Reaction time: 4 h
Yield: 42.4 %

Procedure:
1.14 g (4.08 mmol) of N-(1,1-dimethyl-4-indanyl)-2-chloroacetoacetamide and 0.30 g (4.08 mmol) of thioacetamide were dissolved in 10 ml of tetrahydrofuran and was refluxed for 3 hours. To the reaction mixture was added 0.56 g (4.08 mmol) of anhydrous potassium carbonate and reaction was effected for 4 hours under reflux. The resulting solution was added to water and extracted with ethyl acetate. The organic layer was concentrated and then purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 0.52 g of N-(1,1-dimethyl-4-indanyl)-2,4-dimethylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: [CH2:1]=O.[C:3]([O:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C[O-].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[C:3]([O:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH3:1])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Yield: 103.5 %

Procedure:
Paraformaldehyde (0.15 g, 0.5 mmol) was added in one portion to pressure vessel containing [1-(4-amino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.12 g, 0.34 mmol) in Methanol (5 ml) at room temperature. To this mixture was added sodium methoxide (0.055 g, 1.02 mmol) in one portion, the pressure vessel was sealed and heated at 70° C. for 12 hours. After this time the reaction was cooled to room temperature and sodium borohydride (0.031 g, 0.82 mmol) added in one portion, the pressure vessel was re-sealed and heated at 70° C. for 1 hour. The reaction was then cooled to room temperature, diluted with DCM (20 ml) and washed with water (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.13 g, 99% yield) as a white solid which was taken on without further purification. Tr=1.96 min m/z (ES+) (M+Na+) 392.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][CH:13]([CH3:18])[O:12][C:8]2[N:9]=[C:10]3[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC(CCC=O)Oc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)Oc1ccc2c(n1)NC(=O)CC2
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
To a solution of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (450 mg, crude) in DCE (10 mL) was added 2,3-dichlorophenyl-piperazine hydrochloride (495 mg, 1.85 mmol) followed by Et3N (0.55 mL, 3.96 mmol). The mixture was stirred for 10 min and then powdered NaBH(OAc)3 (534 mg, 2.52 mmol) was added. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give a foam. Purification by liquid chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (507 mg, 1.09 mmol, 61%). MS: APCI: M+1: 463.1 (Exact Mass: 462.16). The enantiomers were separated by chiral HPLC (Chiralcel OD).
Reaction SMILES: [CH3:1][Mg]I.[CH2:4]([O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C:18](=[CH:19][CH2:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C@H:15]1[OH:28])[CH3:5].[NH4+].[Cl-]>C(OCC)C>[CH2:4]([O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C:18](=[CH:19][CH2:20][C:21]([OH:27])([CH3:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C@H:15]1[OH:28])[CH3:5]
Reactant: CCCCCC(=O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(C)(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl magnesium iodide (prepared from 816 mg. magnesium filings and 2.12 ml. methyl iodide) dissolved in 80 ml. dry diethyl ether is added dropwise to 3.9 g. 9β-hydroxy-15-oxo-12-prostenoic acid ethyl ester, dissolved in 200 ml. dry diethyl ether, with the exclusion of moisture, under nitrogen and with stirring. The mixture is stirred for 15 minutes more at room temperature and mixed dropwise, with ice cooling, with 300 ml. saturated aqueous NH4Cl solution. The organic phase is separated, washed with water and dried over Na2SO4. The solvent is removed by distillation to yield as residue 9β,15-dihydroxy-15-methyl-12-prostenoic acid ethyl ester, which is separated chromatographically (first silica gel/dichloromethane:acetone = 10:1; then silica gel/petroleum ether:ethanol = 9:1) into the two 15-epimers;
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[OH:16])=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:27]>>[NH2:27]/[C:5](/[C:4]1[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=1[CH2:1][CH3:2])=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1
Reactant: N
Reactant: CCc1ccccc1C(=O)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCc1ccccc1/C(N)=C1\Sc2ccccc2C1=O
Yield: 46 %

Procedure:
Prepared as in Example 1 from 2-(ethyl-benzoyl)benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 46% of theory. M.p. 132°-133° C. (ethyl acetate/petroleum ether 1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[C:34]([NH2:35])=[C:33]([NH2:36])[C:31](=[O:32])[NH:30][C:28]1=[S:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:35][C:34]1[N:27]([CH2:26][C:25]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:24]=2)[C:28](=[S:29])[NH:30][C:31](=[O:32])[C:33]=1[NH:36][C:10](=[O:11])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OCc1ccccc1
Reactant: CC(C)(OCc1ccccc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(N)c(NC(=O)C(C)(C)OCc3ccccc3)c(=O)[nH]c2=S)cc1OCc1ccccc1
Yield: 75.3 %

Procedure:
A solution of 2-benzyloxy-2-methyl-propionyl chloride (30.70 g, 144 mmole) in THF (100 ml) was added at 0-5° C. over 15 minutes to a stirred suspension of 1-(3-benzyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil (40.58 g, 100 mmole) and triethylamine (31.4 ml, 225 mmole) in THF (400 ml). After 1 hour the solid was filtered off and the solution evaporated to dryness in vacuo. The residue was suspended in a mixture of diethyl ether (400 ml), water (100 ml) and saturated sodium bicarbonate solution (60 ml). After crystallization for 60 hours the solid was collected and washed with ether and water to give 6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-5-(2-benzyloxy-2-methyl-propionylamino)-2-thiouracil (42.23 g, 75.3%). Crystallization from ethyl acetate gave mp 123-125/184-187° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH3:12][N:9]1[CH2:8][CH2:7][C:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C)CC2)cc1

Procedure:
1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8.7 g, 25.6 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.23 g (41%); white solid; mp 204° C.; MS: 313.9 (M+H)+.
Reaction SMILES: N[C:2]1[C:3]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:4]=2[C:5]2[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.N([O-])=O.[Na+].[C:23]([Cu])#[N:24]>Cl>[CH3:18][N:15]1[CH2:16][CH2:17][C:3]2[C:2]([C:23]#[N:24])=[CH:11][C:10]3[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6][C:5]=3[C:4]=2[CH2:14]1
Reactant: N#C[Cu]
Reactant: CN1CCc2c(N)cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CN1CCc2c(C#N)cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
The product from Example 79 is treated with sodium nitrite in 37% HCl solution at 0° C. The reaction mixture is poured into a solution of CuCN and the title compound is isolated by filtration.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 2-chloro-5-methoxyaniline (23 mg, 0.144 mmol) similar to Example 92 and isolated as a white solid (11 mg, 48%). 1H NMR (CDCl3): 8.84–8.82 (m, 1H), 8.58–8.54 (m, 1H), 7.90–7.85 (m, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.46–7.41 (m, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.01 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1.[CH3:28][CH2:29][O-:30].[Na+]>C(O)C>[CH2:29]([O:30][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1)[CH3:28]
Reactant: Cc1nc(-c2ccccc2)nc2sc3c(N4CCNCC4)nc(Cl)nc3c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)nc(C)c3c2n1

Procedure:
1.30 g (3.3 mmol) 2-chloro-9-methyl-4-piperazin-1-yl-7-phenyl-thieno[2,3-d:4,5-d′]di-pyrimidine and 0.67 g (9.9 mmol) sodium ethylate are refluxed in 30 ml ethanol for 3 h. Thereafter, the solvent is removed and the residue is suspended in some water. The aqueous suspension is extracted with dichloromethane and the solvent is removed. 0.90 g (68%) of the title substance is obtained. ESI-MS [m/z]: 407, melting point: >310° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[C:16](Cl)(=[O:18])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:16](=[O:18])[CH3:17])=[C:3]2[C:7](=[CH:8][C:9]=1[O:13][CH3:14])[C:6](=[O:15])[CH2:5][CH2:4]2
Reactant: CC(=O)Cl
Reactant: COc1cc2c(c(N)c1OC)CCC2=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c(NC(C)=O)c1OC)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
4-Amino-5,6-dimethoxy-indan-1-one (Intermediate U) (0.214 g, 1.0 mmol) was taken up into 5 mL of DMF and acetyl chloride(0.071 mL, 1.0 mmol) and DIEA (0.18 mL, 1.0 mmol) were added. The reaction stirred overnight at room temperature. The reaction was quenched with sat. sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and removed in vacuo. 0.25 g of the crude material was produced (Intermediate V); MS m/z 250.1 (M+H)+.