Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][OH:25])[CH3:2].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CO.O>[CH3:32][S:33]([OH:35])(=[O:20])=[O:34].[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][OH:25])[CH3:2]
Reactant: CS(=O)(=O)Cl
Agent: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCO
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Reaction time: 2 h

Procedure:
Stir a cooled solution of 344 mg. of dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene in 2 ml. of pyridine (acetone-dry ice bath) and add dropwise 0.14 ml. of methanesulfonyl chloride. After 2 hours bring reaction mixture to room temperature. Mix with ice and water and a few drops of methanol to obtain a crystalline precipitate. Recrystallize this to obtain dl- 13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene methane sulfonate from methanol (310 mg); m.p. 104°.
Reaction SMILES: C(O)(=O)C.[Si]([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH:20]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:37][CH3:38])(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH:20]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:37][CH3:38]
Reactant: CCOP(=O)(CC(Nc1cccnc1)c1cc(C)c(O[Si](C)(C)C(C)(C)C)c(OC)c1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOP(=O)(CC(Nc1cccnc1)c1cc(C)c(O)c(OC)c1)OCC
Temperature: 20 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Glacial acetic acid (130 ml) was added to 500 ml of a THF solution containing a mixture of diethyl β-(4-t-butyldimethylsilyloxy-3-methoxy-5-methylphenyl)-β-[N-(3-pyridyl)-amino]-ethylphosphonate (90.5 g, 0.18 mol) and tetrabutylammonium fluoride trihydrate (TBAF) (224.5 g, 0.71 mol). After stirring at 20° C. for 3 h a GLC test showed that the Tbs protected compound has entirely reacted. The reaction mixture was extracted with dichloromethane, the organic phase was washed with a saturated bicarbonate solution, dried over MgSO4 and evaporated. Purification by column chromatography (silica gel, 9/1 CH2Cl2/MeOH) gave 53 g of pure fractions. Recrystallization from a mixture of petroleum ether/CH2Cl2 gave 27 g (39%) of the title compound as a white solid, mp=156-158° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([F:19])=[C:4]([F:20])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:20])=[C:5]([F:19])[C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3.18 g, 8.77 mmol) in THF-MeOH (16 mL/5 mL) was added TMSCHN2 (5.30 mL, 10.6 mmol, 2 M solution in hexanes) at room temperature. The resulting mixture was stirred for 1 hour, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (3.31 g, 100%) that was used directly without further purification.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][CH2:13][O:14]C(=O)C)=[C:6](Br)[CH:5]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:10][C:8]1[CH:9]=[C:4]([C:3]([OH:2])=[O:19])[CH:5]=[C:6]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=2)[C:7]=1[O:11][CH2:12][CH2:13][OH:14]
Reactant: COC(=O)c1cc(F)c(OCCOC(C)=O)c(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(F)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 5-fluoro-6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to the compound of step 1 of example 355 in analogy to step 1 of example 3, and the obtained ester intermediate hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7](O)=[O:8].C(OC(=O)C)(=O)C>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:12](=[O:14])[O:13][C:7](=[O:8])[C:6]2=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Yield: 74.7 %

Procedure:
4-Trifluoromethyl-phthalic acid (106.6 g.) and acetic anhydride (215 cc.) are heated to the reflux temperature for 30 minutes. After concentration under reduced pressure (30 mm Hg), the residue is stirred with cyclohexane (420 cc.). After filtration and drying, 4-trifluoromethyl-phthalic anhydride (73.5 g.) melting at 54° C is obtained.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Br:28][Si](CC)(CC)CC.C(=O)([O-])O.[Na+]>ClCCl.[Bi](Br)(Br)Br>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC[Si](Br)(CC)CC
Agent: Br[Bi](Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
β-D-Galactose pentaacetate (5.00 g, 12.8 mmol) and bismuth(III) bromide (287 mg, 640 μmol) were dissolved in dichloromethane (25 mL), the solution was added with bromotriethylsilane (6.76 mL, 51.2 mmol), and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. The reaction mixture was poured into aqueous saturated sodium hydrogencarbonate cooled on ice, then the mixture was extracted with dichloromethane, and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, and the solvent was removed to obtain 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (5.30 g, quantitative).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][C:19]=1[CH:20]=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:20][C:19]2[CH:22]=[C:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:18]=2[O:17][CH3:16])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccncc2)cc1C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccncc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
A stirred suspension of amine (295) (131 mg, 0.61 mmol) and aldehyde (296) (130 mg, 0.61 mmol) in THF (1 mL) and toluene (1 mL) was treated with AcOH (42 μL, 0.73 mmol) at RT. After stirring 1.5 h, the resultant suspension was treated with sodium triacetoxyborohydride (181 mg, 0.86 mmol) and stirred for 18 h. The reaction was diluted with aqueous NaHCO3 and extracted into EtOAc. The organic phase was dried (Na2SO4), filtered, the solvent removed in vacuo and the residue chromatographed with 10% MeOH in EtOAc to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:23](O)=[O:24].[CH:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:21]([O:20][C:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[C:23]([NH:34][CH2:33][CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[N:8]=2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: NCCC1CCCCC1
Reactant: CCOC(=O)C1CCN(c2ccc3c(C(=O)O)c(Cl)ccc3n2)CC1
Product: CCOC(=O)C1CCN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 70.8 %

Procedure:
Prepared according to the method of example 4(a), using 6-chloro-2-[4-(ethoxycarbonyl)-1-piperidinyl]-5-quinolinecarboxylic acid (example 76(c)) (217 mg) and cyclohexaneethanamine (277 mg). Purification (SiO2, methanol:dichloromethane 1:99 as eluant) gave the title compound as a solid (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18].[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=1
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1Cl
Yield: 13 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)-benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). A further purification step using preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2) gave the desired compound as a colorless oil (13%). MS (ESI): m/z=561.052 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=2[NH2:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=3[N:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(C#N)cc2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(C#N)ccc3[nH]2)CC1
Temperature: 0 °C

Procedure:
A solution of 4-(2-amino-4-cyano-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (6 g) in EtOH (61 mL) and 2M aq. NaOH solution (61 mL) was heated at 75° C. (bath temperature) overnight. The heating was discontinued, the reaction was chilled (ice water bath) and quenched by pouring into saturated aq. citric acid solution (250 mL). The mixture was extracted with CH2Cl2 (5×) and the combined organic extract was dried (Na2SO4), filtered and concentrated in vacuo.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.C1COCC1.Br[CH2:29][C:30]1[C:39]2[O:38][CH2:37][CH2:36][O:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>[NH4+].[Cl-]>[O:35]1[CH2:36][CH2:37][O:38][C:39]2[C:30]([CH2:29][N:18]3[CH2:17][CH2:16][CH2:15][C:14]4([CH2:21][CH2:22][N:11]([C:2]5[CH:3]=[N:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=5)[CH2:12][CH2:13]4)[C:19]3=[O:20])=[CH:31][CH:32]=[CH:33][C:34]1=2
Reactant: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: BrCc1cccc2c1OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc3c2OCCO3)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
To a solution of 9-quinoxalin-2-yl-2,9-diaza-spiro[5.5]undecan-1-one (50 mg, 0.169 mmol) in THF (2 ml) sodium hydride 95% (6.07 mg, 0.253 mmol) was added and the mixture was stirred for 20 min. Then 5-bromomethyl-2,3-dihydro-benzo[1,4]dioxin (77 mg, 0.337 mmol) was added and the reaction mixture was heated at 50° C. over 18 h. Saturated aqueous NH4Cl solution (50 ml) was added and the reaction mixture was extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (EtOAc/hexane 70:30) to yield 60 mg (79%) of the title compound. [1H NMR (600 MHz, DMSO-d6) δ 1.54-1.66 (2H, m) 1.76-1.84 (2H, m) 1.87-1.93 (2H, m) 2.02-2.12 (2H, m) 3.23 (2H, t) 3.39-3.47 (2H, m) 4.20-4.23 (2H, m) 4.24-4.27 (3H, m) 4.27-4.30 (1H, m) 4.41 (2H, s) 6.54 (1H, m) 6.72-6.75 (1H, m) 6.75-6.79 (1H, m) 7.32-7.41 (1H, m) 7.49-7.63 (2H, m) 7.80 (1H, d, J=8.07 Hz), 8.82 (1H, s), LCMS RtD=3.27 min, [M+H]+=445.2].
Reaction SMILES: [C:1]([C:3](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8]1)[C:4]([NH2:6])=[O:5])#[N:2].[CH2:17](OC(OCC)(OCC)C)[CH3:18]>CN(C)C=O>[CH3:17][C:18]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:16])[C:8]=12
Reactant: N#CC(C(N)=O)=C1C=C(O)c2ccccc21
Reactant: CCOC(C)(OCC)OCC
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)c2c1C(=O)c1ccccc1-2

Procedure:
A mixture of 1 part of 2-cyano-2-(3-hydroxy-1H-inden-1-ylidene)acetamide, 1 part of 1,1,1-triethoxyethane, and approximately 6 parts of N,N-dimethylformamide is heated at 90°-95° under reflux for 2 hours, whereupon the precipitate which forms is filtered out, washed with ethyl acetate, and dried in vacuo. Crystallization from ethyl acetate affords needles of 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carbonitrile melting above 300°. The product has the formula ##STR7##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[I:32])[C:27]#[N:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:24]1[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][C:31]=1[I:32])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1I)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.16 g (32.8 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of toluene. 10.5 g (42.7 mmol) of 3-hydroxy-4-iodobenzonitrile, 11.2 g (42.7 mmol) of triphenylphosphine and 7.4 g (42.7 mmol) of N,N,N′,N′-tetramethylazodicarboxyamide were added to the solution under cooling with ice, and they were stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by the silica gel column chromatography (volume ratio of hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:22]([OH:24])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:26])[CH2:6]1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:22]([OH:24])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:26])[CH2:6]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(C)=O)C3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21
Yield: 90 %

Procedure:
A solution of 7-(3-acetylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.88 g) in 10% sodium hydroxide (15 ml) was heated to reflux for 5 hours with stirring. The solution was neutralized with 20% hydrochloric acid to give a precipitate, which was collected, washed successively with water and ethanol, dissolved in 10% acetic acid, and adjusted to pH 7.5-8.0 with 10% aqueous ammonia. There were obtained 0.70 g of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 259°-262° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:30][CH3:31])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:32][CH3:33])[CH:6]=1.CO.CO.C(Cl)(Cl)Cl>C(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:30][CH3:31])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:32][CH3:33])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(Cl)cc1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(Cl)cc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (37 mg, 0.077 mmol from Example 94) was purified using chiral SFC to afford 10.5 mg of peak A (Example 94A) and 13.6 mg of peak B (Example 94B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 20 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in 50:50 methanol/chloroform (multiple stacked injections), tR (peak A)=5.3 min, tR (peak B) 14.9 min. The absolute stereochemistry of individual enantiomers (Examples 94A and 94B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 94).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]=[C:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([NH:25][C:45]([CH:43]2[CH2:44][C:41](=[CH2:40])[CH2:42]2)=[O:46])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C=C1CC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)C1

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (690 mg, 1.99 mmol) was dissolved in 6.0 mL of CH2Cl2 followed by the addition of EDC (600 mg, 2.98 mmol) and HOBT (300 mg, 1.99 mmol). 3-Methylenecyclobutanecarboxylic acid (300 mg, 2.59 mmol) was dissolved in 1.0 mL of CH2Cl2 and added to the homogenous reaction mixture. After 24 h the reaction was concentrated in vacuo and dissolved in EtOAc and the organic layer was washed with sat. NaHCO3. The organic layer was washed with H2O and brine. The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAc: Hex] to obtain the desired product as a white fluffy solid; 1H NMR (400 MHz, CDCl3): δ=2.82-2.92 (m, 2H), 2.99-3.06 (m, 2H), 4.77-4.80 (m, 2H), 6.81 (d, 1H, J=7.8 Hz), 7.45-7.54 (m, 3H), 7.83-7.88 (m, 3H), 8.10 (d, 2H, J=7.1 Hz), 8.22-8.23 (brm, 1H), 8.39 (d, 1H, J=1.79 Hz), 8.59 (d, 1H, J=2.5 Hz); MS (ES+): 440.93 (M+1), 442.91 (M+3).
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[N:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=4)=[CH:55][N:54]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([O:42]C)=[O:41]>>[CH3:74][CH:38]([CH3:37])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[N:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=4)=[CH:55][N:54]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([OH:42])=[O:41]
Reactant: CCCCCc1ccc(C(=O)Nc2cnc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cn2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2cnc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cn2)cc1
Yield: 60.34 %

Procedure:
The compound of example 511 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 510.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CCO.O>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=[N:21][OH:22])[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)N1CCCC(=O)c2ccc(Cl)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N1CCCC(=NO)c2ccc(Cl)cc21
Temperature: 60 °C
Yield: 96.1 %

Procedure:
To a solution of 8-Chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (3.40 g, 12.1 mmole) in EtOH/H2O (96.0 ml/24.0 ml) was added hydroxylamine hydrochloride (8.39 g, 121 mmole) followed by sodium acetate (9.93 g, 121 mmole). The reaction was heated under 60° C. for 3 hours. The mixture was partitioned between ethyl acetate (100 ml) and 1.00N HCl (100 ml). After separated the two layers, the aqueous layer was extracted with more acetate (2×100 ml). The combined organics washed with NaHCO3 (aq) and followed by brine (2×200 ml). Dried over Na2SO4, filtered and concentrated to provide the crude product (3.45 g, 96%), which was used directly for the next step without further purification. MS (ES+): 297 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:5][C:4](=O)[C:3]=1[CH:13]([CH3:15])[CH3:14].O(C)[Na].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]([CH:13]([CH3:15])[CH3:14])=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)[nH]c(=O)c1C(C)C
Agent: CO[Na]
Product: Cc1nc(C(F)(F)F)nc(Cl)c1C(C)C
Yield: 58 %

Procedure:
6-Methyl-5-(2-propyl)-2-trifluoromethyl-4H-pyrimidin-4-one of Example 3 (1.66 g, 7.5 mmol) was converted to a Na salt with NaOCH3 then refluxed with phosphorus oxychloride (6 mL) for 3 h. The reaction mixture was concentrated to a small volume, poured into crushed ice, and extracted with Et2O. The organic layer was washed with H2O (twice), dried over Na2SO4, and evaporated to give 1.05 g (58%) of a light yellow oil.
Reaction SMILES: [Mg].Br[CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[CH3:8][C:9](=[CH:12][CH2:13][CH3:14])[CH:10]=[O:11]>CCOCC>[CH3:8][C:9]([CH:10]([OH:11])[CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:12][CH2:13][CH3:14]
Reactant: CCC(Br)CC
Reactant: CCC=C(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(CC)CC

Procedure:
A Grignard reagent, prepared by reacting 29.4 g (1.21 g atoms) of magnesium in 200 ml of ether and 183 g (1.21 mol) of 3-bromopentane in 400 ml of ether, is reacted with 98.0 g (1.0 mol) of 2-methyl-2-pentenal in a manner analogous to Example 5. Fractional distillation of the crude product (159.3 g) over a 20 cm Widmer column gives 95.5 g (56.2%) of olfactorily good 4-methyl-6-ethyl-3-octen-5-ol of melting point 92°-93° C./12 mm Hg.