Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.F[C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:7][C:5]1([F:8])[CH2:4][C@H:3]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)[C@@H:2]([NH:1][C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][N:25]=2)[CH2:6]1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC(F)(F)C[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 50 mg, 0.15 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 29 mg, 0.16 mmol) and DIPEA (26 μl, 0.15 mmol) in dry DMSO (485 μl). The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C.N1CCCCC1>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2c(I)cccc2N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Temperature: 23 °C
Yield: 65.2 %

Procedure:
A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (404.1 mg, 1.56 mmol) (see Fukuyama et al., supra) and pyrrole-2-carboxaldehyde (163.2 mg, 1.72 mmol) (Aldrich) in 2-propanol (6.2 mL) was treated with 2 drops of piperidine. The reaction mixture was heated at reflux for 24 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The solid was washed several times with cold distilled water and then allowed to air dry to provide pure (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (341.8 mg, 65%) as a yellow solid which was used without further purification. (MP 256-258° C.).
Reaction SMILES: C(O[C:4]([C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[O:16][CH:17]([F:19])[F:18])=[O:5])C.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:15][C:11]1[C:10]([O:16][CH:17]([F:18])[F:19])=[C:9]2[C:14]([C:4]([OH:5])=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=CNc1cccc(F)c1OC(F)F)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2c(OC(F)F)c(F)ccc2c1O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 10.0 g (0.029 mole) of N-(2,2-diethoxycarbonylvinyl)-3-fluoro-2-difluoromethoxyaniline obtained as described above and 70 ml of diphenyl ether was refluxed by heating for 30 minutes. The mixture was cooled to room temperature, and n-hexane was added thereto. Crystals precipitated were collected by filtration and dried to obtain 5.25 g of ethyl 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylate as white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.ClCCl>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:11])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)N2CCCC2)c(C)c1
Temperature: 50 °C

Procedure:
25.0 g (124 mmol) N-acetyl-4-amino-2-methyl-benzoic acid are combined with 3 drops DMF in 1000 ml dichloromethane and a solution of 21.0 ml (30.56 g, 241 mmol) oxalyl chloride in 100 ml TEA is added dropwise with stirring and cooling in the ice bath. Then the mixture is heated to 50° C. for 4.5 hours. The reaction mixture is filtered and the filtrate is evaporated down completely i. vac. The residue is taken up in 100 ml dichloromethane and this solution is added dropwise to a mixture of 10.4 ml (8.86 g, 125 mmol) pyrrolidine and 34.4 ml (25.0 g, 247 mmol) TEA in 500 ml dichloromethane with stirring and cooling in the ice bath. The mixture is stirred for 16 hours at ambient temperature. After filtering the filtrate is washed with 1-molar hydrochloric acid and sat. sodium chloride solution, combined with activated charcoal and dried over sodium sulphate. After evaporation i. vac. the residue is purified by chromatography on silica gel.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:18])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].CCOCC.[Li+].[OH-].Cl>O.CO>[O:18]=[C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])[C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1CCN1C(=O)C(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: O=C(C(=O)N1CC[C@H]1C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of (2S)-methyl-1-(1,2-dioxo-2-phenylethyl)azetidine-2-carboxylate from Reference Example 9 (522.5 mg; 2.11 mmol) in a 1:1 mixture of ether:methanol (20.0 mL) was added 1N LiOH in water (3.9 mL) at about 0° C. The mixture was stirred under argon at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1N HCl and then the mixture was diluted with water and extracted with dichloromethane. The organic layers were then washed with brine, dried over sodium sulfate and concentrated to give 415.2 mg (67% yield) of the product as a yellow solid. 1H NMR (CDCl3) δ 2.33-2.91 (series of m, 2H); 4.08-4.51 (series of m, 2H); 5.09 and 5.31 (dd, 1H, J=10.3, 6.9, J=10.3, 6.9); 7.40-7.73 (m, 3H); 8.04-8.19 (m, 2H); 8.25-8.80 (br, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:33]=[N+:34]=[N-:35])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-(−)-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 6, 13.83 g) and sodium azide (7.62 g) in dry dimethylformamide (117 mL) under N2 is stirred at 60° C. for five hours and at ambient temperature for 16 hours. The mixture is then diluted with ethyl acetate (200 mL), washed with water (8×100 mL) and saline (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound, mp 109-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:7]5[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: COc1nn(C)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1nn(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 27.6 %

Procedure:
In the same manner as in Example 259 and using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (93 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.72 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (59 mg, 28%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([O:4][CH2:3][CH:2]([NH2:1])[CH3:5])=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
50.0 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 29.3 g of 60% sodium hydride and 300 mL of N,N-dimethylformamide at 0° C. After the reaction mixture was stirred for 30 minutes at 0° C., a solution containing 121.2 g of 4-bromobenzonitrile dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The resultant mixture was stirred for 20 hours at room temperature. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was distilled under reduced pressure to obtain 48.0 g of the desired product (yield 41%). Boiling point: 132° C./0.26 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:15](OCC)=[O:16]>C(OCC)C>[O:16]=[CH:15][CH:9]([C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1cc(C)cc(Cl)c1
Reactant: CCOC=O
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1cc(C)cc(Cl)c1
Yield: 61.4 %

Procedure:
Prepared analogously to the method described in Example N(v) above from ethyl 3-chloro-5-methylphenylacetate (4.89 g; 23 mmol; from step (iv) above), ethyl formate (3.3 g; 41.4 mmol) and Na (0.63 g; 27.6 mmol; added in small lumps) in dry ethyl ether (50 mL) to yield 3.4 g (61%) of the sub-title compound as a clear oil which slowly crystallised on standing.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18]([O:20]CC)=[O:19])[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[C:18]([OH:20])=[O:19])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Temperature: 120 °C
Yield: 88.1 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (1.00 g, 2.93 mmol), in 2:1 tetrahydrofuran:methanol (15 mL) was added 1 N aqueous sodium hydroxide (4.40 mL, 4.40 mmol). The solution was heated in a microwave reactor to 120° C. for 500 seconds. Then 1 N aqueous hydrochloric acid (4.40 mL, 4.40 mmol) was added and the solution was concentrated. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and dried under a nitrogen stream at 45° C. overnight to afford 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl) -4-isoxazolecarboxylic acid (808 mg, 88%). 1H-NMR (400 MHz, DMSO-d6) δ 13.34 (br s, 1H), 8.81 (s, 2H), 4.33-4.25 (m, 1H), 2.42-2.32 (m, 4H), 2.15-2.05 (m, 1H), 1.96-1.88 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH:22]1([CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][NH2:32])[CH2:24][CH2:23]1.C(N(CC)CC)C>C(OCC)(=O)C>[NH3:4].[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][C@@H:27]2[CH2:28][CH2:29][CH2:30][N:26]2[CH2:25][CH:22]2[CH2:24][CH2:23]2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NC[C@@H]1CCCN1CC1CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NC[C@@H]2CCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Product: N
Yield: 175.4 %

Procedure:
A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (400 mg, 1.22 mmol) and [(2S)-1-(cyclopropylmethyl)pyrrolidinyl]methylamine (WO 87,07271) (190 mg, 1.22 mmol) and triethylamine (0.51 ml, 3.67 mmol) in ethyl acetate (20 ml) was heated under reflux for 18 hrs. The cooled mixture was partitioned between water and ethyl acetate, the phases separated, and the organic layer dried over MgSO4 and concentrated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as eluant to give the desired product as a yellow oil, (476 mg, 88%).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7](O)[CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>C1(C)C=CC=CC=1.CO.[Pd]>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:8]([CH3:54])[CH2:7][CH2:6][C:5]1=[O:56])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Yield: 40.7 %

Procedure:
To a solution of 17-Allyl-1,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg) in toluene (20 ml) was added p-toluenesulphonic acid (5 mg) and the resulting solution was warmed for 90 minutes on a steam bath. Evaporation of volatiles in vacuo and chromatography of the residue on silica eluting with ethyl acetate gave an oil which was dissolved in methanol (5 ml). To this was then added 10% palladium-on-carbon (20 mg) and the mixture was stirred in an atmosphere of hydrogen for 1 hour at room temperature. The reaction mixture was then filtered through celite, concentrated in vacuo and purified by chromatography on silica eluting with ethyl acetate to give the title compound as an oil (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1.[OH:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2>>[CH3:18][C:14]1[N:13]=[C:12]([NH:11][CH:5]([C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[C:21]2[C:20]([OH:19])=[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=[N:28]3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1cccc(N)n1
Reactant: Oc1cccc2cccnc12
Product: Cc1cccc(NC(c2ccc(F)c(F)c2)c2ccc3cccnc3c2O)n1

Procedure:
The title compound was prepared by method B presented for the compound of Example 1 with the change that 3,4-difluorobenzaldehyde was reacted with 2-amino-6-picoline and 8-hydroxy-quinoline. White powder precipitated, C22H17F2N3O, (MW: 377.1); yield; 275 mg (53.3%). m.p.: 162-165° C.; HPLC (CH3CN/H2O 70:30 Phenomenex C18 282 nm): 7.97 min.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:21](=O)[CH3:22])[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18].N1CCOCC1.BrC1C=CC2OC(C(NC3[S:43]C=C(C4C=CC(Cl)=CC=4)C=3C(O)=O)=O)=NC=2C=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[S:43][CH:22]=[C:21]([C:13]2[CH:12]=[C:11]([O:10][CH3:9])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=C(Nc1scc(-c2ccc(Cl)cc2)c1C(=O)O)c1nc2cc(Br)ccc2o1
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: CCOC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)csc1N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Ethyl cyanoacetate (5 mmol), and 1-(3,4,5-trimethoxyphenyl)ethanone (5 mmol) are dissolved in toluene (5 mL). Morpholine (5 mmol) is added followed by activated molecular sieves (4A). The reaction is stirred at 80° C. for 12 hours. The reaction is cooled to room temperature, filtered and concentrated. The residue is taken up in toluene (5 mL), ethanol (5 mL) and sulfur is added (0.16 g; 5 mmol). The reaction mixture is heated with mixing at 70° C. for 12 hours. The reaction is cooled to room temperature and the solvents are evaporated. The residue is purified by HPLC to provide ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiophene-3-carboxylate. Ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiophene-3-carboxylate (5 mmol) is treated with 4-methylbenzoyl chloride (5 mmol) in THF (10 mL). The reaction is stirred at room temperature for 10 hours. The reaction is diluted with 1N NaOH (10 mL) and ethyl acetate (15 mL). The layers are separated, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography to provide ethyl 4-p-tolyl-2-(3,4,5-trimethoxybenzamido)thiophene-3-carboxylate. Ethyl 4-p-tolyl-2-(3,4,5-trimethoxybenzamido)thiophene-3-carboxylate is hydrolyzed under a variety of conditions (e.g. LiOH, water; LiOH, H2O2, water; or NaOH, water) to provide the title compound
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:15]3[N:20]=[C:19]([NH:21][C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=3)=[CH:3][C:2]2=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Yield: 60.9 %

Procedure:
Following a procedure analogous to 61e, 12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (100 mg, 0.57 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (170 mg, 0.57 mmol) were converted to the title compound as an off-white solid (151 mg, 61%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.3 (s, 1H), 8.8-8.7 (m, 2H), 8.3 (s, 1H), 7.8 (d, 1H, J=7.8 Hz), 7.5 (t, 1H, J=7.6 Hz), 7.3-7.2 (m, 2H), 7.1 (t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=7.8 Hz), 4.0 (m, 1H), 3.7 (m, 1H), 3.0 (dd, 1H, J=16.3, 4.8 Hz), 2.8 (d, 3H, J=4.0 Hz), 2.7-2.6 (bs, 1H), 2.4 (d, 1H, J=16.3 Hz), 1.9-1.8 (m, 2H), 1.7 (m, 1H), 1.5-1.4 (m, 1H); MS (m/e) 435 (M+1); mp 209-212° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][C:3]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1.[ClH:30].[NH2:31][OH:32].N1C=CC=CC=1.CO>C(O)(=O)C>[ClH:30].[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:31][OH:32])=[CH:4][C:3]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22][C:23]([CH3:25])([CH3:26])[CH2:24]2)=[CH:16][CH:17]=1
Reactant: CN(c1ccc(-c2cc3c(cc2O)C(=O)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: CN(c1ccc(-c2cc3c(cc2O)C(=NO)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a microwave vial was added 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (Example 35-1,150 mg, 0.38 mmol), hydroxylamine hydrochloride (264 mg, 3.80 mmol), pyridine (0.25 mL, 3.04 mmol) and MeOH (1.0 mL). The resulting suspension was stirred at RT for 1.5 hours. The reaction mixture was acidified with excess acetic acid and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford the title compound. MS [M+H+]=410.2, LCMS Rt=0.48 min [Method Q]; 1H NMR (400 MHz, DMSO-d6) ppm 10.94-11.13 (m, 1H), 8.91-9.21 (m, 1H), 8.29 (d, J=10.04 Hz, 1H), 8.09-8.21 (m, 1H), 7.83 (s, 1H), 7.52-7.73 (m, 1H), 7.08 (s, 1H), 4.83-5.31 (m, 1H), 2.91-3.04 (m, 5H), 2.74-2.85 (m, 2H), 1.91-2.09 (m, 2H), 1.79 (d, J=10.79 Hz, 2H), 1.53 (s, 6H), 1.47 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7](COCC[Si](C)(C)C)[N:6]=[CH:5]2.N1CCCCC1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (543 mg, 0.819 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 10 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. After washing with several volumes of methanol, the product was eluted with 2M ammonia in methanol. Concentration gave the crude piperidine. The piperidine was dissolved in dichloromethane (5 mL) and treated with di-tert-butyl dicarbonate (224 mg, 1.02 mmol). After 1 h, the reaction was quenched by addition of 2M ammonia in methanol and concentrated. The residue was suspended in water and extracted with diethyl ether. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (EtOAc/Hex) gave 420 mg (96%). 1H-NMR (CDCl3, 500 MHz) δ 10.05 (bs, 1H), 7.89 (s, 1H), 7.71 (d, J=1.8, 1H), 7.23 (m, 2H), 7.08 (d, J=1.5, 1H), 7.02 (m, 2H), 4.48 (q, J=6.7, 1H), 3.70 (m, 2H), 3.34 (d, J=9.2, 1H), 3.23 (d, J=8.9, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.21 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.72 (m, 1H), 1.41 (s, 9H), 1.40 (d, J=6.7, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 162.6, 160.6, 155.0, 138.1, 135.9, 133.7, 128.7 (d, J=7.7), 127.9, 126.5, 125.5, 122.3, 115.7, 115.6, 113.6, 79.6, 78.6, 78.0, 41.2, 40.1, 32.5, 32.1, 28.5, 22.2, 14.3.