Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:24]=[CH:23][S:22][C:17]=5[N:18]=[C:19](Cl)[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])O1.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>[CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:24]=[CH:23][S:22][C:17]=5[N:18]=[C:19]([C:33]5[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=5)[C:36]([O:38][CH3:39])=[O:37])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1nc(Nc2cccc(N3CC4(COC4)C3)c2)c2ncsc2n1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Yield: 30.5 %

Procedure:
To a solution of N-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (160 mg, 0.5 mmol) and methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (145 mg, 0.55 mmol) in 9 mL of 1,4-dioxane and 1 mL of water was added Na2CO3 (159 mg, 1.5 mmol) followed by Pd(PPh3)4 (58 mg) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation. The residue was poured into water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether EtOAc=1:1) to give methyl 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (70 mg, 30%). LC-MS: 460 [M+H]+, tR=1.74 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>CN(C)C(=O)C>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=1)[CH3:9])=[O:6])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(NC(=O)c1ccnc(N)c1)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)C(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a mixture of 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.073 mmol, Step-1, single enantiomer) and pyridine (0.024 mL, 0.29 mmol) in N,N-dimethylacetamide (1 mL) is added isobutyryl chloride (16 mg, 0.15 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture is poured onto water (2 mL), and the mixture is extracted with ethyl acetate (3 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then by preparative LC-MS to give 12.9 mg (43% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:27][CH2:28][O:29][C:5]2=[CH:4][CH:3]=1.[C:30](OC([O-])=O)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[C:33]([O:32][C:30]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:17]2[CH:16]=[C:15]([OH:26])[CH:14]=[C:13]3[C:18]=2[C:9]([NH:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]4[O:29][CH2:28][O:27][C:6]=24)=[N:10][CH:11]=[N:12]3)[CH2:25][CH2:24]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Oc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Yield: 69.1 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazoline (1.4 g), di-(tert-butyl dicarbonate (0.737 g) and DMF (14 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 24:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (1.2 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.7-1.9 (m, 2H), 2.0-2.15 (m, 2H), 3.0-3.15 (m, 2H), 3.8-3.95 (m, 2H), 4.6 (m, 1H), 6.02 (s, 2H), 6.55 (s, 1H), 6.72 (d, 1H), 6.98 (m, 2H), 8.4 (s, 1H), 9.4 (s, 1H); Mass Spectrum: M+H+ 515 and 517.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][C@@H:12]([NH2:14])[CH3:13].Cl[C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:43][C:26]2=[CH:27][C:28]3[C:29](=[O:42])[N:30]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[C:31](=[O:34])[C:32]=3[CH:33]=[C:25]2[N:24]=1>>[CH3:41][N:38]1[CH2:39][CH2:40][CH:35]([N:30]2[C:29](=[O:42])[C:28]3[CH:27]=[C:26]4[NH:43][C:23]([C:17]5[C:18](=[O:22])[NH:19][CH:20]=[CH:21][C:16]=5[NH:14][C@@H:12]([CH3:13])[CH2:11][C:3]5[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=5[F:10])=[N:24][C:25]4=[CH:33][C:32]=3[C:31]2=[O:34])[CH2:36][CH2:37]1
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: C[C@H](N)Cc1c(F)c(F)cc(F)c1F
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
(S)-1-(2,3,5,6-Tetrafluorophenyl)propan-2-amine and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione were submitted to general procedure A. The isolated solid was triturated with water once and MeOH four times to give the title compound as an off-white solid, which was used directly in the next step.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][N:3]=[N:2]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1([CH2:6][C:7]([Cl:13])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1cnnn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cn1cnnn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(1H-tetrazol-1-yl)acetic acid 3 (1 gm, 7.81 mmol) in benzene (20 mL) was added oxalyl chloride (1.5 g, 11.81 mmol) and a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under vacuum and the crude acid chloride 4 obtained was used for the next step without any purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:28](=[O:29])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 132, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 96 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (31%). MS (ESI): m/z=560.08 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:30](Br)(=[O:32])[CH3:31]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18]([O:27][C:30](=[O:32])[CH3:31])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Br
Reactant: O=C(NCCCN1CCC(O)(c2ccccc2)CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1(c2ccccc2)CCN(CCCNC(=O)OCc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
To a solution of N-benzyloxycarbonyl-3-(4-hydroxy-4-phenylpiperidin-1-yl)propylamine (0.5 g, 1.36 mmol) in THF (20 mL) at 0° C., sodium hydride (60% suspension in paraffin, 65 mg, 1.63 mmol, 1.2 eq.) was added and the mixture was stirred for 1.5 h. To this acetyl bromide (0.12 mL, 1.63 mmol) was injected and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 h. Solvent was evaporated, the residue was mixed with dichloromethane (100 mL), and washed with water (2×20 mL). Solvent was evaporated from the dried dichloromethane solution gave the product as a viscous oil (0.485 g, 87%). The 1H-NMR showed this product to be pure and was used in the next step without any further purification.
Reaction SMILES: O[CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[CH:4]1.CN(C)C=O.S(Cl)([Cl:17])=O>C(Cl)(Cl)(Cl)Cl>[Cl:17][CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: OCn1cnc(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: ClCn1cnc(Cl)c1Cl
Yield: 77.1 %

Procedure:
94 g of 1-hydroxymethyl-4,5-dichloroimidazole is dissolved in 550 ml of carbon tetrachloride. 1 ml of dimethylformamide is added, and 100.5 g of thionyl chloride is dripped in while stirring. The mixture is refluxed until no more gas evolves, after which the solvent is removed under reduced pressure and 750 ml of methylene chloride and 250 ml of water are added to the residue. While the mixture is stirred thoroughly, its pH is brought to 7.5 with 5% strength aqueous sodium hydroxide solution. The organic phase is then separated, washed with water and dried over sodium sulfate. The residue remaining after removal of the solvent is distilled at 92° to 95° C./0.1 mbar. There is obtained 80.5 g (77%) of 1-chloromethyl-4,5-dichloroimidazole; m.p.: 40°-41° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[N:20][C:21](F)=[C:22]([CH3:24])[CH:23]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[C:22]([CH3:24])[C:21]([N:29]5[CH2:30][CH2:31][O:27][C:28]5=[O:32])=[N:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cnc1F
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCOC3=O)c(C)c2)CC1
Yield: 33.8 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-5-methylpyridin-3-yl)methanone (500 mg) described in Preparation Example 147 and oxazolidin-2-one (246 mg), the title compound (201 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8](=[CH:14][NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](F)[C:3]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1ccc(Br)c(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(Br)ccc2c1=O
Temperature: 25 °C
Yield: 96.9 %

Procedure:
In 7 ml of dimethyl sulfoxide was dissolved 0.72 g of ethyl 2-(4-bromo-2-fluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate, followed by adding thereto 0.48 g of potassium carbonate, and the resulting mixture was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to room temperature, after which 35 ml of water was added thereto and the crystals were collected by filtration to obtain 0.66 g of colorless ethyl 7-bromo-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1
Reactant: CC(=O)Nc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(N)cc(-c2ccccc2)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of N-(5-nitrobiphenyl-3-yl)acetamide (1.2 g, 4.68 mmol) in THF (10 ml) were added a solution of ammonium chloride (2 g, 37.4 mmol, 8 eq.) in water (2 ml) and zinc (2.36 g, 37.4 mmol, 8 eq.). The mixture was stirred at 45° C. for 2 h and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 94% yield (1 g).
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[C:20]([F:29])[C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([CH:30]2[CH2:32][CH2:31]2)[CH:17]=1)=[O:15])C.C(N(CC)CC)C>N1C=CC=CC=1>[CH:30]1([N:18]2[C:19]3[C:24](=[CH:23][C:22]([F:27])=[C:21]([N:8]4[CH2:9][CH2:10][C:6]5([O:5][CH2:4][CH2:3][CH2:2][O:1]5)[CH2:7]4)[C:20]=3[F:29])[C:25](=[O:26])[C:16]([C:14]([OH:15])=[O:13])=[CH:17]2)[CH2:31][CH2:32]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1COC2(CCNC2)OC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC4(C3)OCCCO4)c(F)cc2c1=O

Procedure:
A 0.276 g (1.8 mmol) sample of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2 Example 14, 0.400 g (1.29 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (preparation described by K. Grohe, et al., DE 3318145, November 1984) and 0.52 mL (3.7 mmol) of triethylamine and 12 mL of pyridine were heated at 65° C. for 48 hours in dry glassware and under dry nitrogen. The solvent was evaporated and the ester purified by chromatography on a silica gel column using as eluant 0.5% methanol in methylene chloride increasing to 2% methanol in methylene chloride. The solvent was removed to afford 0.218 g of the title compound, which was taken to the next step directly.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([C@H:5]1[CH2:6][C@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[C@@H:8]([O:10][CH3:11])[CH2:9]1)=[O:4]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: CO[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1S,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-cyclopentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methoxy-cyclopentyl}-amide. Yellow solid. MS: 490.0 ([M+H]+).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH:32]=O>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:32][C:24]5[N:23]([CH3:22])[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[N:25]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Reactant: Cn1c(C=O)nc2ccccc21
Product: C[C@@H]1CN(Cc2nc3ccccc3n2C)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 1-methyl-1H-benzo[d]imidazole-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.98 (s, 1H), 7.73 (m, 1H), 7.35 (dd, J=7.1, 1.2 Hz, 1H), 7.29-7.21 (m, 2H), 5.13-5.09 (m, 1H), 4.11-4.06 (m, 2H), 3.97 (s, 3H), 3.37 (t, J=8.3 Hz, 1H), 3.06 (d, J=10.4 Hz, 1H), 2.88-2.85 (m, 1H), 2.77-2.73 (m, 1H), 2.16-1.92 (m, 8H), 1.70-1.66 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). MS: (M+H m/z=432.1).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
A stirred solution of bis (2-chloroethyl) amine hydrochloride (150 g, 0.84 mol), potassium carbonate (255 g, 1.9 mol) and benzyl bromide (110 ml, 0.92 mol) in DMF (1500 ml) was heated at 100° C. for 1 hour. The mixture was allowed to cool to ambient temperature, then the DMF removed in vacuo. The residue was taken into ethyl acetate (1000 ml), then washed with water (2×1000 ml). The organic phase was separated, dried (MgSO4) and evaporated. The crude residue was chromatographed in 20:1 petrol:ether, to give N-benzyl bis(2-chloroethyl)amine (36 g, 18%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:27])=[CH:15]/[C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:27])=[CH:15]/[C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:37])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CSCCOc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C/C(=C\c1ccc(OCCS(C)=O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
2.1 g of the compound obtained in Example 5 are dissolved in 50 ml of chloroform and treated slowly at 0° with a solution of 1.2 g of m-chloroperbenzoic acid (90%) in 10 ml of chloroform. After stirring at 0° for 20 hours the mixture is washed with dilute soda solution and water, dried and evaporated. The thus-obtained yellow oil is filtered over a small silica gel column (eluting agent hexane/ethyl acetate=1:2) and recrystallized from ethyl acetate. There are obtained 1.7 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl sulphoxide, melting point 134°-136°.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1O)(=[O:3])[CH3:2].[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH2:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCN
Solvent: CCO
Product: CC(=O)N[C@H]1C(CCCCCCCCCCCCN)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
15 g of N-acetylglucosamine and 19 g of dodecylamine are heated at 80° C. for 3 hours in 50 ml of ethanol, with stirring. The undissolved material is then filtered off hot, the filtrate is cooled and the precipitated product is filtered off with suction and rinsed with ethanol and ether. The residue on the filter is dried in vacuo.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]>C(O)(=O)C.ClCCl>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(O)c(OC)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc(OC)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of fuming nitric acid (12.1 ml; s.g. 1.5) in glacial acetic acid (120 ml) was added in one portion to a stirred solution of 4-ethyl-2-methoxyphenol (41.7 g) in dry dichloromethane (800 ml). After 1 minute the solution was washed with water (3×300 ml), and the organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give an orange crystalline residue. This was recrystallised from a mixture of methanol and water to give 4-ethyl-2-methoxy-6-nitrophenol (31.3 g), m.p. 59°-61° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[N:7][NH:6][C:5](=O)[CH:4]=1.O=P(Cl)(Cl)[Cl:14]>O1CCOCC1>[Cl:14][C:5]1[N:6]=[N:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)cn[nH]1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnnc(Cl)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
5-(Trifluoromethyl)pyridazin-3(2H)-one (20.0 g, 111 mmol) was dissolved in 1,4-dioxane (222 mL) and POCl3 (31.0 mL, 333 mmol) added. The reaction was left to stir at 80° C. for 3 h. After consumption of the starting material, the reaction was cooled to room temperature. The reaction mixture was added to ice and quenched with ammonium hydroxide. The aqueous layer was extracted with dichloromethane (×3) and the organic layers combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as an orange oil. 1H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H); 7.76 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[F:13].[F:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([F:23])[C:16]=1[CH:24]([O:28][CH2:29][CH3:30])[C:25](O)=[O:26]>>[C:8]([C:7]1[CH:6]=[C:5]([F:13])[C:4]([CH2:3][NH:2][C:25](=[O:26])[CH:24]([C:16]2[C:15]([F:14])=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=2[F:23])[O:28][CH2:29][CH3:30])=[C:11]([F:12])[CH:10]=1)#[N:9]
Reactant: N#Cc1cc(F)c(CN)c(F)c1
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Agent: Cl
Product: CCOC(C(=O)NCc1c(F)cc(C#N)cc1F)c1c(F)cc(OC)cc1F

Procedure:
According to general procedure C 4-aminomethyl-3,5-difluoro-benzonitrile hydrochloride was reacted with (RS)-(2,6-difluoro-4-methoxy-phenyl)-ethoxy-acetic acid (example 101.3) give to (RS)-N-(4-cyano-2,6-difluoro-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Off-white solid. MS 397.1 ([M+H]+)