Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]1=2.[ClH:28].[BH3-]C#N.[Na+].C[OH:34]>>[OH2:34].[ClH:28].[ClH:28].[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]1=2.[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]1=2.[ClH:28].[ClH:28]
Reactant: CO
Reactant: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2)Nc2cccnc21
Product: O

Procedure:
A solution of 3.0 g (0.0064 mole) of N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in absolute methanol was adjusted to pH 5.6 with methanolic hydrogen chloride solution. To this solution was added at one time, 0.7 g (0.011 mole) of NaBH3CN and the reaction mixture was refluxed for 20 min. The ethanol was removed in vacuo and the residue was partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated to leave a residue which was twice crystallized from 2-propanol and isopropyl ether. A yellow solid, 1.6 g (57%) was obtained which loses its crystalline structure on heating starting at 156°-160° C. with decomposition at 180°-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([Cl:20])=O>>[ClH:20].[F:13][C:14]([F:24])([F:25])[C:15]1[CH:16]=[C:17]([C:18]2[NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]4[C:11]=3[C:10]([N:12]=2)=[CH:9][CH:8]=[CH:7]4)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: Cl
Product: FC(F)(F)c1cccc(C2=Nc3cccc4cccc(c34)N2)c1
Yield: 95.4 %

Procedure:
1,8-Diaminonaphthalene (15.82 g.; 0.10 mole) and m-trifluoromethylbenzoyl chloride (20.8 g.; 0.10 mole) were reacted in the same procedures as reported in Example 1, yielding 33.3 g. (95.4% yield) of 2-(m-trifluoromethylphenyl)-1H-perimidine hydrochloride, m.p. 280° C. (dec), mass spectrum m/e 312.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:8][CH2:9][CH2:10][CH2:11][CH:12](Br)[CH2:13][CH3:14]>CN(C)C=O>[Br-:8].[CH2:9]([N+:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N+:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-:8]
Reactant: CCC(Br)CCCBr
Reactant: CN1CCCCC1
Solvent: CN(C)C=O
Product: C[N+]1(CCCCCC[N+]2(C)CCCCC2)CCCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-methylpiperidine (˜73.3 g), 1,4-dibromohexane (˜82 g), and dimethylformamide (˜250 mL) were combined and stirred at room temperature for about 24 hours. The solid product was filtered and then washed with diethyl ether (˜750 mL). After drying the product (˜106 g, ˜71%) was confirmed to be 1,1′-(hexane-1,6-diyl)bis(1-methylpiperidin-1-ium) bromide by 1H NMR.
Reaction SMILES: Cl[CH:2]1[NH+:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[C:9]([CH3:23])[C:8]2[CH:7]=[CH:6][C:5]([O:24][CH3:25])=[C:4]([O:26][CH3:27])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3.[Cl-].[CH2:29]([Mg]Br)[CH3:30].O1CC[CH2:35][CH2:34]1>C(OCC)C>[CH2:34]([C:2]1([CH2:29][CH3:30])[N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[C:9]([CH3:23])[C:8]2[CH:7]=[CH:6][C:5]([O:24][CH3:25])=[C:4]([O:26][CH3:27])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3)[CH3:35]
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1OC)C(Cl)[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Reactant: CC[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Product: CCC1(CC)c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a suspension of 8-chloro-9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; chloride (1050 mg, 2.5 mmol) in anhydrous diethyl ether (50 mL) at 0° C. was added a solution of ethylmagnesium bromide in tetrahydrofuran (3 M, 9 mL, 27.4 mmol) dropwise. After stirring at 0° C. for 20 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8,8-diethyl-9,10-dimethoxy-13-methyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (220 mg, 21%).
Reaction SMILES: N#N.Cl.C[CH:5]1[C:13]2[C:8](=[C:9]([N+:16]([O-])=O)[C:10]([NH2:15])=[C:11](Br)[CH:12]=2)[CH2:7][CH:6]1[NH2:19].[C:20]([OH:25])(=O)[C:21](O)=[O:22].[CH3:26]O>[Pd]>[CH3:26][NH:19][CH:6]1[CH2:7][C:8]2[C:9]3[NH:16][C:20](=[O:25])[C:21](=[O:22])[NH:15][C:10]=3[CH:11]=[CH:12][C:13]=2[CH2:5]1
Reactant: O=C(O)C(=O)O
Reactant: CC1c2cc(Br)c(N)c([N+](=O)[O-])c2CC1N
Reactant: CO
Agent: [Pd]
Agent: Cl
Agent: N#N
Product: CNC1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of N2 -methyl-2,5-diamino-6-bromo-4-nitroindane hydrochloride (17.2 g, 53 mmol) and 20% Pd/C (1 g) in methanol (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 6 h. After removing the catalyst, the filtrate was evaporated and the residue taken up in 2N HCl 250 mL) and oxalic acid (13 g, 0.1 mmol) and heated at 100° C. for 5 h. The mixture was cooled in a refrigerator overnight, and the resulting precipitate was collected by filtration and washed with water and then diethyl ether and dried to give the product (9.9 g).
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[C:1]([N:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CC(O)C1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccccc2)C1

Procedure:
To a stirred mixture of 2.5 g. of N-benzoyl-3-azetidinol, 21 g. of triethylamine in 35 ml. of DMSO, add rapidly, in a dropwise manner, a suspension of 7.0 g. of pyridine sulfur trioxide in 35 ml. of DMSO and stir for 15 minutes. Remove most of the DMSO in vacuo at 60° C and chromatograph the residue on 100 g. of silica gel. Elute with chlorform and collect 2.4 g. of the crude compound of this example from the front running yellow band. Recrystallize from isopropyl ether.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:25](O)=[O:26]>>[F:19][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:30]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=1
Reactant: COc1ncccc1-c1ccncc1NCC(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1ncccc1-c1ccncc1N(CC(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 (2,2-difluoro-ethyl)-(2-methoxy-[3,4]bipyridinyl-3′-yl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 67 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (64%). MS (ESI): m/z=507.11 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]1[NH:44][CH2:43][CH2:42][N:41]2[CH2:45][CH2:46][CH2:47][CH2:48][CH:40]12>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:43][CH2:42][N:41]4[CH2:45][CH2:46][CH2:47][CH2:48][CH:40]4[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCN2CCNCC2C1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN2CCCCC2C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with octahydro-pyrido[1,2-a]pyrazine (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C39H49N4O2Cl2 [(M+H)+] 675.3227, observed 675.3224.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11].Cl>C1COCC1.O.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1

Procedure:
LiOH.H2O (222 mg, 5.29 mmol) was added to a stirred solution of phenylmethyl 5-bromo-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 4, method A; 700 mg, 1.76 mmol) in THF (15 ml) and water (5.00 ml). The mixture was refluxed for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a yellow solid. 400 mg.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:36][CH:37]=1)[CH3:27]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>>[CH2:37]([O:36][C:34]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[CH:13][N:12]=2)[CH2:32][CH2:31]1)=[O:35])[CH2:38][CH3:39]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and propyl chloroformate (Aldrich) to give 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propyl ester. MS (M+H)+, 432.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:35]([CH2:39][CH2:40][CH2:41][CH3:42])[C:36](Cl)=[O:37])[CH2:32][CH2:33][CH3:34].O1CCCC1>C(OCC)(=O)C.O>[CH2:31]([N:35]([C:36]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:37])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:32][CH2:33][CH3:34]
Reactant: On1c(-c2ccccc2)nc2c3ccc4ccccc4c3ccc21
Reactant: CCCCN(CCCC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)On1c(-c2ccccc2)nc2c3ccc4ccccc4c3ccc21

Procedure:
10 parts of 1-hydroxy-2-phenylphenanthroimidazole, 8 parts of anhydrous potassium carbonate and 6.7 parts of N,N-dibutylcarbamyl chloride in 100 parts of tetrahydrofuran are refluxed for 5 hours. 100 parts of water and 200 parts of ethyl acetate are then added. The organic phase is washed with water, dried over sodium sulfate and evaporated down under reduced pressure. When the residue is left to stand, 6.6 parts of a solid which has a melting point of 120° C. and is pure according to thin layer chromatography are obtained.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([C:22]([CH3:24])=[CH2:23])[C:14]2=[O:25])=[CH:9][CH:8]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:53][C@H:52]([CH2:51][O:50][C:47]1[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=1)[CH2:54][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([C:22]([CH3:24])=[CH2:23])[C:14]2=[O:25])=[CH:11][CH:12]=1
Reactant: C=C(C)n1c(=O)n(-c2ccc(CCN)cc2)c2ncccc21
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C(C)n1c(=O)n(-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)c2ncccc21
Yield: 28.3 %

Procedure:
3-[4-(2-Aminoethyl)phenyl]-1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one formate (0.32 g, 0.96 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.433 g, 1.07 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.19 g, 0.272 mmol).
Reaction SMILES: [CH3:1][Mg+].[Br-].C(C1C=C[C:9]([F:15])=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2)#N.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[C:18]([C:17]1[CH:16]=[CH:20][C:9]([F:15])=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2)(=[O:19])[CH3:1]
Reactant: C1CCOC1
Reactant: C[Mg+]
Reactant: N#Cc1ccc(F)c2cc[nH]c12
Agent: [Br-]
Product: CC(=O)c1ccc(F)c2cc[nH]c12
Temperature: -18 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To an oven dried 250 ml flask was charged with CH3MgBr (16.7 ml, 50 mmol, 3 M in Et2O) at r.t. under N2. It was then cooled down to −18° C. in a NaCl/ice bath, and 7-cyano-4-fluoroindole (2.0 g, 12.5 mmol) in dry THF (100 ml) was added dropwise using an addition funnel over 45 min. After 10 min, the reaction mixture was allowed to warm to r.t., and stirred for 2 hr. The reaction was slowly quenched with 5% sulfuric acid and the mixture stirred for 10 min. The reaction mixture was concentrated in vacuo and the residue poured into CHCl3 (150 ml). After neutralization with aqueous NH3 (50 ml), water (100 ml) was added, and the two layers were separated using a separation funnel. The aqueous layer was back extracted with CHCl3 (2×100 ml), and the combined organic extracts washed with H2O (100 ml), brine (100 ml), and dried (MgSO4). After evaporation in vacuo, the resulted crude compound was purified by flash chromatography (20% EtOAc/Hexane) to give 7-acetyl-4-fluoroindole (1.3 g, 59%) as a light gray solid. 1H NMR: (CDCl3) δ 10.55 (b s, 1H), 7.76 (dd, J=4.8, 8.3, 1H), 7.31 (app t, J=2.7, 1H), 6.83 (dd, J=8.4, 9.6, 1H), 6.67 (app t, J=2.9, 1H), 2.68 (s, 3H); HPLC Rt=1.343.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=C[C:28]=1[O:34][CH3:35])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.COC1C(B(O)O)=CC=C[N:40]=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:36])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[C:28]([O:34][CH3:35])=[N:40][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ncccc1B(O)O
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ncccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (83%). MS (ESI): m/z=266.11 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](F)=[N:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:15]=1[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=O.[NH2:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:10]2[C:11](=[N:12][C:13]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:14][C:15]=2[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])[NH:32][N:31]=1
Reactant: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc(F)c1C(=O)c1ccccc1Cl
Reactant: NN
Product: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12

Procedure:
Crude (S)-(2-Chloro-phenyl)-[6-(2,4-difluoro-phenoxy)-2-fluoro-4-(2-hydroxy-propylamino)-pyridin-3-yl]-methanone (837 mg, 1.92 mmol) was treated with hydrazine using the procedure of step 5 of Example 9 to afford 148 mg of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-propan-2-ol. Mass spec., M+1=432. Mp=237.9
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)=O.[CH3:17][NH:18][NH2:19]>CCO>[CH3:1][O:2][C:3]([C:4]1[N:18]([CH3:17])[N:19]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[CH:5]=1)=[O:16].[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[N:18]([CH3:17])[N:19]=1)=[O:16]
Reactant: COC(=O)C(=O)CC(=O)c1cccc(Br)c1
Reactant: CNN
Solvent: CCO
Product: COC(=O)c1cc(-c2cccc(Br)c2)n(C)n1
Product: COC(=O)c1cc(-c2cccc(Br)c2)nn1C
Temperature: 65 °C
Yield: 37 %
Yield: 28 %

Procedure:
3.00 g (10.52 mmol) of 4-(3-bromo-phenyl)-2,4-dioxo-butyric acid methyl ester were suspended in 16 ml of EtOH and 0.485 g (10.52 mmol) of methylhydrazine were added. The reaction was heated under reflux (65° C.) for 5 h. Then the solvent was evaporated and the residue was partitioned between aqueous 1N HCl/EtOAc (3×). The organic phases were washed with aqueous sat. NaCl, dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography (SiO2, n-heptane/EtOAc 99:1) to give 1.64 g (37%) of 5-(3-bromo-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (and ethyl ester) as white powder (MS: methyl ester 295.1 MH+, 1 Br; ethyl ester 309.1 MH+, 1 Br) and 1.11 g (28%) of 5-(3-bromo-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (and ethyl ester) as yellow oil (MS: methyl ester 295.1 MH+, 1 Br; ethyl ester 309.1 MH+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:8][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:42][O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)=[O:25])[CH:16]=4)[O:11]3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Yield: 81.1 %

Procedure:
A suspension of (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (300 mg, 0.74 mmol) in DCM (9 ml) was treated with TEA (0.17 ml, 1.2 mmol) and then with EDC (235 mg, 1.23 mmol), HOBt (166 mg, 1.23 mmol) and NH2OTHP (115 mg, 0.982 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (280 mg) as a light yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH2:25][N:24]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=O)[C:23](=[O:32])[C:22]=1[C:33]1[CH:37]=[CH:36][S:35][CH:34]=1.[Cl:38][C:39]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:40]=1[NH2:41].C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.ClCCl>[Cl:38][C:39]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:40]=1[NH:41][C:27](=[O:29])[C:26]([N:24]1[CH2:25][C:21]([CH3:20])=[C:22]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[C:23]1=[O:32])([CH3:31])[CH3:30]
Reactant: CC1=C(c2ccsc2)C(=O)N(C(C)(C)C(=O)O)C1
Reactant: Nc1cc(Cl)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=C(c2ccsc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)ccc2Cl)C1
Temperature: 70 °C
Reaction time: 24 h
Yield: 22.7 %

Procedure:
Triphenylphosphine (1.3 g) was added to a suspension of 2-[4-methyl-2-oxo-3-(thiophen-3-yl)-3-pyrrolin-1-yl]isobutyric acid (1 g) in carbon tetrachloride (9 mL) and dichloromethane (9 mL), and the mixture was heated at reflux for 30 minutes at 70° C. After ice-cooling the reaction solution, 2,5-dichloroaniline (0.61 g) and then triethylamine (0.38 g) were added, and the mixture was stirred for 24 hours at room temperature. After the reaction was completed, distilling off the solvent, water was added and the resulting mixture was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and a saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous sodium sulfate. After distilling off ethyl acetate, the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: chloroform/ethyl acetate=20/1) to give 0.35 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([CH:31]3[CH2:30][CH2:29][CH:28]([C:23]4[C:22]5[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=5)[NH:25][CH:24]=4)[CH2:33][CH2:32]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: FC(F)(F)c1cccc(N2CCCNCC2)c1
Product: Fc1ccc2c(C3CCC(N4CCCN(c5cccc(C(F)(F)F)c5)CC4)CC3)c[nH]c2c1
Yield: 64 %

Procedure:
The title compound was prepared according to Example 3, Step 4 except 1-(3-trifluoromethyl-phenyl)-[1,4]diazepane was used instead of 1-(2-methoxy-phenyl)-[1,4]diazepane and 4-(6-fluoro-1H-indol-3-yl)-cyclohexanone was used in place of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone. Yield: 64%; MS (ES) m/z (relative intensity): 460 (M++H, 100).