Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.CO[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]=1>>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][N:9]=[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20]2)=[CH:5][CH:4]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COC1=NCCCCC1
Agent: Cl
Product: Clc1ccc(CCN=C2CCCCCN2)cc1
Reaction time: 72 h

Procedure:
A slurry of 15.9 g (0.08 mole) of p-chlorophenethylamine hydrochloride in 25 ml of O-methylcaprolactim is allowed to stand at room temperature 3 days with occasional stirring with a glass rod. The mixture is then cooled and the resulting solid is collected, washed with ether and recrystallized from methanol-acetone to give 2-(p-chlorophenylethylimino)hexahydroazapine hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccncc2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 7-(2-(pyridin-4-yl)-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 4)(65 mg, 0.142 mmol) in THF (3 ml) and water (1 ml) was treated with LiOH (33.9 mg, 1.417 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and the residue was diluted with water and washed with EtOAc (×2). The aqueous was acidified (1 N HCl, pH ˜5) and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to a yellow gum which was triturated with ether to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[N:6]([CH3:22])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.9 %

Procedure:
A mixture of 4-chloro-1-(2,4-dimethylphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (0.30 g, 1.10 mmol), MeI (0.075 ml, 1.21 mmol), potassium carbonate (0.30 g, 2.2 mmol) and DMF (5 ml) was stirred at room temperature for 13 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 0.31 g (98%) of the title compound as crystals.
Reaction SMILES: Cl.[CH:2]1([NH:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[O:16][N:15]=[C:14]([CH2:17][CH2:18][CH3:19])[N:13]=3)[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[C:30]1[O:34][CH:33]=[N:32][CH:31]=1)[C:24](O)=[O:25]>>[CH:2]1([N:5]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[O:16][N:15]=[C:14]([CH2:17][CH2:18][CH3:19])[N:13]=3)[CH2:8][CH2:7]2)[C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([C:30]3[O:34][CH:33]=[N:32][CH:31]=3)=[C:21]([F:20])[CH:22]=2)[CH2:3][CH2:4]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: CCCc1noc(N2CCC(NC3CC3)CC2)n1
Agent: Cl
Product: CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine hydrochloride and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.20 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]1[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:22][C:12]2=1)=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:41]([NH:43][NH2:44])[CH3:42]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])=[CH:22][C:12]3=2)[N:43]([CH2:41][CH3:42])[N:44]=1)=[O:34])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n(CC)n1

Procedure:
930 mg (1.85 mmol) of compound A 4-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2,4-dioxobutyric acid ethyl ester are dissolved in 20 ml of absolute ethanol. 583 mg (5.56 mmol) of ethylhydrazine oxalate are added and the mixture is refluxed overnight. The reaction medium is evaporated to dryness and the residue is triturated in a saturated K2CO3 solution. The product is filtered and washed with water. Purification is carried out on a silica column, elution being carried out with EtOAc.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.ClC1C2C=C(N(C)C)N=CC=2N=CN=1.N>C(O)C.ClCCl>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: CN(C)c1cc2c(Cl)ncnc2cn1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)cc1

Procedure:
4-(2-Pyridylmethoxy)aniline was prepared from 4-nitrophenol (Aldrich) and 2-picolyl chloride hydrochloride (Aldrich) according to Procedure D. This was reacted with 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine according to Procedure A to give the product; tlc (dichloromethane:ethanol:aq.ammonia, 100:8:1) Rf 0.37; m/z (M+1)+373.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](OC)=[O:13])=[CH:7]2.COCCO[AlH2-]OCCOC.[Na+].O.Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][OH:13])=[CH:7]2
Reactant: COC(=O)c1ccc2c(Br)cccc2c1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: OCc1ccc2c(Br)cccc2c1
Yield: 89.5 %

Procedure:
Methyl 5-bromo-2-naphthoate (6.0 g) in benzene (100 ml) was cooled at 7° and a 70% solution of Vitride (sodium dihydro bis-2-methoxyethoxy aluminate) (10 ml) in benzene (20 ml)) was added dropwise with stirring. The solution was stirred for 4 hours at this temperature and decomposed with water and dilute hydrochloric acid. The benzene solution was separated and washed successively with dilute acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated to give a solid (4.8 g), m.p. 76°-77°.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][C:24]=3[CH2:32][CH2:33][CH2:34][CH3:35])=[O:22])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.O.Cl>C1COCC1>[CH2:32]([C:24]1[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:23]=1[C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:36])=[O:4])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1)=[O:22])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(OCC(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1 N NaOH (721 μL, 0.721 mmol) was added under nitrogen to a solution of methyl[(4′-{[(2-butyl-1-benzofuran-3-yl)carbonyl]amino}[1,1′-biphenyl]-4-yl)oxy]acetate (300 mg, 0.656 mmol), prepared in the previous step, in 30 mL of THF plus 10 mL of water at room temperature. After the addition the reaction was stirred at room temperature for 18 h (overnight). The reaction was acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (188 mg, 65%) as a white solid, mp 225-227° C.; MS (APCI) m/z 444 [M+H]+. Elemental Analysis for C27H25NO5.0.07 H2O: Calc'd: C, 72.92; H, 5.70; N, 3.15; Found: C, 72.45; H, 5.64; N, 3.06
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)=[O:9]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: COc1ccc(NC(=O)c2cc(Cl)ccc2O)cc1C(F)(F)F
Yield: 79.1 %

Procedure:
Using 5-chlorosalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:16][CH:15]=[CH2:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C

Procedure:
2-Bromo-4-nitrophenol (9.2 g) was dissolved in dimethylformamide (50 ml) and sodium hydride (2.4 g) was added portionwise. The bright yellow solution was stirred until all effervescence ceased. Allyl bromide (4.7 ml) was added and the resulting solution was heated at 60° C. for 30 minutes. The mixture was cooled, quenched by the dropwise addition of water 30 ml, then diluted with water (500 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with sodium hydroxide (2N), water, brine, dried (MgSO4) and evaporated. The residue was purified on silica using 5-10% ethyl acetate in hexane to afford the title compound as a crystalline solid (10 g). 1H NMR (360 MHz, CDCl3) δ 4.72 (2H, d, J=6 Hz), 5.37 (1H, d, J=9 Hz), 5.51 (1H, d, J=15 Hz), 6.94 (1H, d, J=6.5 Hz), 8.18 (1H, dd, J=6.5, 2.6 Hz), 8.47 (1H, J=2.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=3[N:13]=2)=[C:4]([F:29])[CH:3]=1.[N:30]([CH:33]1[CH2:35][CH2:34]1)=[C:31]=[O:32]>>[CH:33]1([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])[C:11]4[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=4[N:13]=3)=[C:4]([F:29])[CH:3]=2)[CH2:35][CH2:34]1
Reactant: O=C=NC1CC1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 47 %

Procedure:
Method as example 113 step 2 using (S)-ethyl 2-(4-amino-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and isocyanatocyclopropane as starting materials. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) yielding the final compound (17 mg, 0.04 mmol, 47%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](I)[CH:20]=[CH:19][N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[Cl:16][C:17]1[CH:22]=[C:21]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1cc(I)ccn1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Product: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1CC1
Yield: 592.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 200 mg, 0.985 mmol) was reacted with 2-chloro-4-iodo pyridine (283 mg, 0.118 mmol) 1,4-dioxane (10 mL), copper iodide (19 mg, 0.0985 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (14 mg, 0.0985 mmol) and potassium phosphate (626 mg, 2.95 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 220 mg of the product (71.10% yield).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Reactant: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 3-ethynyl-N-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.170 mmol) of 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0.009 g (0.008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of CuI, and 0.04 mL (0.23 mmol) of diisopropylethylamine in 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H).
Reaction SMILES: COC([N:5]([C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Cl)(=[O:8])=[O:7])=O.[CH3:38][NH:39][CH3:40]>C(#N)C>[CH3:38][N:39]([CH3:40])[CH2:20][CH2:19][CH2:18][C:17]([NH:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[S:6]([NH:5][C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:8])=[O:7])=[O:22]
Reactant: CNC
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2NC(=O)CCCCl)ccc2c1OCC1CC21
Solvent: CC#N
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2NC(=O)CCCN(C)C)ccc2c1OCC1CC21
Temperature: 40 °C

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-(4-chlorobutyryl-amino)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 109, 0.15 g) and dimethylamine (30% aqueous solution, 5 mL) in acetonitrile (10 mL) was stirred and heated at 40° C. for 10 hours. After cooling, the mixture was concentrated under vacuum and the residue was extracted with a mixture of ethyl acetate and THF (50%), dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by thick layer chromatography on silica, eluting with a mixture of methanol and DCM (10%) to give methyl (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.14 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[C:5]([CH3:19])([CH3:18])[CH2:4][CH2:3]1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:9]([Br:21])[CH:10]=2)[C:5]([CH3:19])([CH3:18])[CH2:4][CH2:3]1
Reactant: BrBr
Reactant: CCCCCCc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
10 g of 1,1,4,4-tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene were dissolved in 100 ml of carbon tetrachloride and, after the addition of a spatula tip of iron powder, treated dropwise at 0° C. with 6.4 g of bromine. After stirring at 0° C. for 3 hours the reaction mixture was poured into ice-water, extracted with ether and, after drying over sodium sulphate, evaporated. The crude product was purified by filtration over a silica gel column (eluent hexane/ethyl acetate=9:1) and gave 13 g of 1,1,4,4-tetramethyl-6-hexyl-7-bromo-1,2,3,4-tetrahydro-naphthalene as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[N:21]=[C:20]([NH2:22])[S:19][N:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([NH:22][C:20]2[S:19][N:18]=[C:17]([CH3:16])[N:21]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nsc(N)n1
Reactant: Clc1ncccc1OCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nsc(Nc2ncccc2OCc2ccccc2)n1
Yield: 89.9 %

Procedure:
3-(Benzyloxy)-2-chloropyridine (0.8393 g, 3.821 mmol), 3-methyl-1,2,4-thiadiazol-5-amine (8.684 mL, 3.474 mmol), potassium phosphate (0.8110 g, 3.821 mmol), tris(dibenzylideneacetone)dipalladium (O) (0.07952 g, 0.08684 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.05527 g, 0.09552 mmol) in toluene (8 mL) and water (3 mL) were reacted according to Example 17, Step B, to afford 3-(benzyloxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-amine (0.932 g, 88.13% yield) as light yellow solid. 1H NMR (CDCl3) δ 8.9 (s, 1H), 7.97 (dd, J=1.17, 5.07 Hz, 1H), 7.37 (m, 5H), 7.15 (dd, J=1.17, 7.80 Hz, 1H), 6.89 (dd, J=5.07, 7.80 Hz, 1H), 5.09 (s, 2H), 2.47 (s, 3H). Mass spectrum (esi) m/z=299 (100) (M+H).
Reaction SMILES: [CH:1]1([C:13]([O:15]C)=[O:14])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][C:8]([C:9]([O:11]C)=[O:10])=[C:2]12.C1(C(OCC)=O)CCN2C=CC(C(OCC)=O)=C12>>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][N:3]2[CH:4]=[CH:5][C:1]([C:13]([OH:15])=[O:14])=[C:2]12
Reactant: COC(=O)c1ccn2c1C(C(=O)OC)CC2
Agent: CCOC(=O)c1ccn2c1C(C(=O)OCC)CC2
Product: O=C(O)c1ccn2c1C(C(=O)O)CC2

Procedure:
Similarly, substituting for the dimethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate of part A of this Example, diethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate, and similar di(lower alkyl) 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates, one obtains 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:14]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:15]2[N:14]=[C:13]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:28]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(C(F)(F)F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-trifluoromethyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(3-trifluoromethyl-phenoxy)-isoquinolin-3-yl]-amine. LC-MS m/e 385(MH+).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:30]=[CH:31][CH:32]=1>ClCCl.CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10]([N:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=1)[CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: COC(=O)CNc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C(=O)CNC(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Boc-glycine and triethylamine (1.0 equiv.) in dichloromethane at 0° C. is added oxalylchloride (1.0 equiv). After one hour, a solution of the product from Step F (1 equiv.) in dichloromethane is added to the first solution, followed by triethylamine (1 equiv.). The solution is allowed to warm to room temperature. After complete reaction, the solution is poured into EtOAc and washed with sat. NH4Cl soln., sat. NaHCO3 soln., and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material is purified by silica gel chromatography to provide the titled compound.
Reaction SMILES: C(N(S(F)(F)F)CC)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:41]#[N:42])=[C:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]([CH:25]([CH:33](O)[CH:34]3[CH2:38][CH2:37][O:36][CH2:35]3)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19](=[O:40])[CH:18]=2)[CH:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:41]#[N:42])=[C:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]([C:25](=[CH:33][CH:34]3[CH2:38][CH2:37][O:36][CH2:35]3)[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:19](=[O:40])[CH:18]=2)[CH:16]=1
Reactant: COc1cn(C(C(=O)OC(C)(C)C)C(O)C2CCOC2)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cn(C(=CC2CCOC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At RT, 0.5 ml (3.8 mmol, 1.2 eq.) of diethylaminosulphur trifluoride was added dropwise to a solution of 1.55 mg (3.13 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-hydroxy-3-(tetrahydrofuran-3-yl)propanoate (diastereomer mixture) in 48 ml of dichloromethane, the mixture was stirred at RT for 90 min and 50 ml of dichloromethane and 50 ml of saturated aqueous sodium bicarbonate solution were then added. After phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield: 1.38 g (93% of theory)