Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:28])[CH:7]=[C:8]([S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[O:9]2)[CH3:2].C(OC([N:36](C(OC(C)(C)C)=O)[CH2:37][C:38](O)=[O:39])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:63]>ClCCl.C(OCC)(=O)C>[ClH:63].[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:28])[CH:7]=[C:8]([S:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:38](=[O:39])[CH2:37][NH2:36])=[CH:23][CH:22]=1)[O:9]2)[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOc1c(OC)c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1c(OC)c(OC(C)C)cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c12
Reaction time: 1 h

Procedure:
300 ml in dichloromethane of 11.35 g of 5-ethoxy-2-(4-hydroxyphenylthio)-7-isopropoxy-6-methoxychromone obtained in Example 18, 5.43 g of N-t-butoxycarbonyl(Boc)glycine, and 6.40 g of dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 1 hour. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 11.28 g of 5-ethoxy-2-(4-glycyloxyphenylthio)-7-isopropoxy-6-methoxychromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:19]1([NH:25][N:26]=[CH:1][C:2]([CH3:3])([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:15])[CH3:16])[NH2:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NNc1ccccc1
Yield: 100 %

Procedure:
The procedure as described in Example 1(b) is followed but with the use of 23.3 g (0.1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene, 20 g of 37% hydrochloric acid, 20 ml of water and 10.8 g (0.1 mol) of phenylhydrazine. On processing as described in Example 1(b), there is obtained 34.1 g (0.1 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal-phenylhydrazone; yield 100% of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1O)=[O:8]>Cl.CO>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]2[C:7](=[O:8])[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[O:17][C:10]=2[CH:11]=1
Reactant: COC(=O)CC(=O)CC(=O)c1ccc(C)cc1O
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cc(=O)c2ccc(C)cc2o1
Reaction time: 2 h

Procedure:
Methyl-5-(2-hydroxy-4-methylphenyl)-3,5-dioxopentanoate is dissolved in a saturated solution of hydrogen chloride in methanol and allowed to stand for 2 hours. The solution is evaporated and the crude product purified by flash chromatography on silica gel to give methyl 2-(7-methyl-4-oxo-4H-1-benzopyran-2-yl)acetate.
Reaction SMILES: [CH:1]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][NH:19]C(=O)C(F)(F)F)[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>O>[CH:1]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NCCCc1cccc(OCC2CCCCCC2)c1)C(F)(F)F
Solvent: CO
Solvent: O
Product: NCCCc1cccc(OCC2CCCCCC2)c1

Procedure:
N-(3-(3-(cycloheptylmethoxy)phenyl)propyl)-2,2,2-trifluoroacetamide was deprotected following the method used in Example 10 except that the MeOH:water mixture was 4:1. After the extractive work up, the residue was dissolved in hexanes, filtered through Celite and concentrated under reduced pressure. Example 14 was isolated in pure form without further manipulation. 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.6 Hz, 1H), 6.70-6.76 (m, 3H), 3.71 (d, J=6.8 Hz, 2H), 2.74 (t, J=7.2 Hz, 2H), 2.62 (t, J=8 Hz, 2H), 1.43-2.02 (m, 15H), 1.23-1.33 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=3)[CH:8]=2)[N:3]=1.C([NH2:28])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:23])[CH3:24])[N:13]=[C:12]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[N:3]=[C:2]([NH2:28])[CH:11]=[CH:10]4)[C:20]=12
Reactant: CC(C)n1nc(-c2ccc3nc(Cl)ccc3c2)c2c(N)ncnc21
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)n1nc(-c2ccc3nc(N)ccc3c2)c2c(N)ncnc21
Temperature: 200 °C
Yield: 45.9 %

Procedure:
3-(2-chloroquinolin-6-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA130, 50 mg, 0.15 mmol), acetamide (174 mg, 3.0 mmol) and K2CO3 (104 mg, 0.75 mmol) were combined and heated to 200° C. under an argon atmosphere for one hour. Reaction was cooled, then extracted with H2O and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA146 (22 mg, 46% yield). ESI-MS (M+H)+ m/z calcd 320.2, found 320.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:35][O:36]C1C=CC(CO)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:36][CH3:35])=[CH:27][CH:26]=2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3cccc(Cl)c3)c2cc1F
Product: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate c, from 1-(3-chloro-benzyl)-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 11, intermediate) and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Off-white powder (87%). MS (Turbo Spray): m/z=492.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][CH:28]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1cc[n+]([O-])cc1
Yield: 87.5 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.140 g, 0.00040 mol) in dimethoxyethane (7 mL) and water (15 mL) was reacted with 4-phenoxyphenylboronic acid (0.093 g, 0.00043 mol), sodium carbonate (0.105 g, 0.00099 mol) and tetrakis(triphenylphosphine)palladium (O) (0.046 g, 0.00004 mol) at 80° C. for 18 hours. The solid was filtered to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.138 g, 0.00035 mol) as a brown solid. A portion (0.040 g, 0.00010 mol) was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 40% isocratic for five minutes, then 40%-100% acetonitrile-0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give the product 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate as a white solid (0.013 g, 0.00003 mol).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.COC1C=CC(C[O:22][CH2:23][C:24]2[CH:25]=[C:26]3[CH2:49][C:31]4([C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[N:33]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:32]4=[O:48])[O:30][C:27]3=[N:28][CH:29]=2)=CC=1>ClCCl.O>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[CH2:49][C:31]3([C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[C:32]3=[O:48])[O:30][C:27]2=[N:28][CH:29]=1
Reactant: COc1ccc(COCc2cnc3c(c2)CC2(O3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(CO)cnc3O2)c2cccnc21
Temperature: 23 °C
Reaction time: 1 h

Procedure:
DDQ (0.533 g, 2.35 mmol) was added to a solution of 5-(((4-methoxybenzyl)oxy)methyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.61 g, 1.2 mmol) in dichloromethane (16 mL) and water (4 mL) at 0° C. The resulting mixture was gradually warmed to 23° C. and stirred for 1 h, then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=400.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[N:3]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2cccc(Cl)c2)c2ccccc12
Yield: 70 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-chlorophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-chlorophenyl)-1H-indole-3-carboxaldehyde (70% yield) as a cream solid. ESI/MS 290 (M+H); RT=3.55 min; NMR 10.13 (1H, s); 8.21 (1H, d); 7.84 (1H, d); 7.74 (3H, m); 7.38 (2H, m); 7.16 (1H, d, J=9 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:3]=1.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOC(C)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)CN
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Step C EXAMPLE 26 (300 mg) in THF (3.3 mL) was added isobutylamine (0.83 mL). The reaction stirred at room temperature overnight at which point LC/MS indicated incomplete reaction. The temperature was elevated to 50° C. for 6 hours at which point the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 15% EtOAc in hexane affording the title compound. HPLC/MS: 396.1 (M+1), 398.1 (M+3); Rt=4.77 min.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 21.8 %

Procedure:
The title compound (45.2 mg) was prepared as in Example 177, Steps C and D, using 269.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 359.2 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C19H22F3N3, 349.49; found, m/z 350.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.87 (d, J=7.9 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 4.48 (m, 1H), 3.43-3.40 (m, 2H), 3.21-3.17 (m, 2H), 2.81-2.77 (m, 2H), 2.07-1.86 (m, 6H), 1.66-1.57 (m, 2H).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:29])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]=1[CH3:28])=[O:13]>C(OCC)(=O)C>[CH3:4][C:5]1([CH3:29])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]=1[CH3:28])=[O:13]
Reactant: O=[O+][O-]
Reactant: CC(C)=CC1C(C(=O)OCc2cccc(-c3ccccc3)c2C)C1(C)C
Solvent: CCOC(C)=O
Product: Cc1c(COC(=O)C2C(C=O)C2(C)C)cccc1-c1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Ozone was bubbled at -78° C. into a solution of 698 mg (2.01 mmol) of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 1, in 10 ml of ethyl acetate. The supply of ozone was terminated when the solution turned slightly blue. Then, 1 ml of dimethyl sulfide was added, and the temperature of the mixture was allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane/hexane=1/1) to obtain 591 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-formylcyclopropanecarboxylate.
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].S(Cl)([Cl:18])=O>>[Cl:18][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][F:1])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCF)c(C(F)(F)F)c1
Product: FCOc1ccc(CCl)cc1C(F)(F)F
Reaction time: 3 h
Yield: 80.3 %

Procedure:
(4-(Fluoromethoxy)-3-(trifluoromethyl)phenyl)methanol (1.84 g, 8.21 mmol) was dissolved in thionyl chloride (8.09 mL, 111 mmol) and stirred for 3 h. The reaction was taken up in hexanes and washed with water (twice), saturated NaHCO3, and water. The organics were dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a solid (1.60 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.83 (s, 2H), 5.83-6.14 (d, J=53.1 Hz, 2H), 7.46 (d, J=8.46 Hz, 1H), 7.69-7.87 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH2:25])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH:25][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (0.66 g, 3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (0.59 g, 3.13 mmol) and N,N-diisopropylethylamine (0.81 g, 6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.11 mg, 9% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=O)([O-:3])=[O:2].[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:18]([C:17](=[O:22])[CH3:16])[C:19](=[O:21])[CH3:20])[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])([O-:3])=[O:2]
Reactant: O=Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 2.12 g of 3,5-dinitro-4-hydroxybenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.9 g, mp 158° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccccc1Cl
Product: CC1(C)CC(=O)c2ccc(-c3ccccc3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2-chlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 271.1; HRMS: calcd for C17H15ClO+H+, 271.08842; found (ESI, [M+H]+), 271.088.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([NH2:11])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1)[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>CN1C(=O)CCC1.O>[CH2:1]([NH:4][C:5]1[C:10]([NH:11][C:18]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[O:19])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1cccs1
Reactant: C=CCNc1ncnc(Cl)c1N
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCNc1ncnc(Cl)c1NC(=O)c1cccs1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
N*4*-Allyl-6-chloro-pyrimidine-4,5-diamine (0.20 g, 0.0011 mol) was taken in NMP (3 ml). Thiophene-2-carbonyl chloride (0.14 ml, 0.0013 mol) was added slowly at 0° C. and stirred for 2 hrs at same temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×5 ml). The organic layer was washed with saturated NaHCO3 solution (10 ml), followed by brine (10 ml) and dried over Na2SO4. The solvent was removed to get thiophene-2-carboxylic acid (4-allylamino-6-chloro-pyrimidin-5-yl)-amide (0.281 g, 88%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][Si](C(C)C)(C(C)C)C(C)C)[CH:14]=3)[N:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:8]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:8]=[C:7]2[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)#[CH:17]
Reactant: CC(C)[Si](C#Cc1ccc2c(c1)c(-c1ccncc1)nn2C(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)c(-c1ccncc1)nn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.1 %

Procedure:
To a solution of tert-butyl 3-(pyridin-4-yl)-5-((triisopropylsilyl)ethynyl)-1H-indazole-1-carboxylate (3.10 g, 6.5 mmol) in THF (100 ml) was added 1M TBAF in THF (7.2 ml, 7.2 mmol). The reaction was stirred for 3 h at room temperature. Upon completion, the reaction mixture was quenched with the addition of saturated aqueous NH4Cl (50 ml) and extracted with Et2O (3×100 ml). The combined organic extracts were washed with saturated aqueous NaCl (100 ml) and dried with anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and column purified (20-80% EtAOc/Hexane) to give the desired product of tert-butyl 5-ethynyl-3-(pyridin-4-yl)-1H-indazole-1-carboxylate (0.77 g) and the de-Boc product of 5-ethynyl-3-(pyridin-4-yl)-1H-indazole (0.40 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12]([NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])(=[O:14])=[O:13])=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Yield: 18 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 5-(2-pyridyl)thiophene-2-sulfonyl chloride (13.5 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 18% yield (3.2 mg). MS (ESI+) calcd mass for C16H12N2O4S2 360.023848, found 360.023668.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:9]=[C:8]([NH:18][C:15]2[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=2)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)c(C#N)cc2Cl)n[nH]1
Temperature: 55 °C
Yield: 59.8 %

Procedure:
To a 25-ml, round-bottom flask, was added 2,5,6-trichloronicotinonitrile (Method 44, 1 g, 4.8 mmol), 5-methyl-1H-pyrazol-3-amine (466 mg, 4.8 mmol), DIEA (1.1 ml, 6.3 mmol), and EtOH (5 ml) and set to heat at 55° C. for 16 hours. The resulting mixture was then purified by silica gel chromatography (Biotage Horizon System) using 25-75% EtOAc/hexanes to give 770 mg of the title compound. 1H NMR: 12.36 (s, 1H) 9.68 (s, 1H) 8.39 (s, 1H) 6.32 (s, 1H) 2.29 (s, 3H). MS: Calcd.: 268. Found: [M+H]+ 267/269.
Reaction SMILES: [F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=3[CH3:23])[NH2:19])[C:3]=12.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:39])([F:40])([F:36])([F:37])[F:38])[CH:34]=1)[C:29]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([N:15]2[C:3]3[N:4]([N:5]=[C:6]([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[F:1])[CH:13]=[CH:14]2)[CH:17]=1)=[O:30])#[N:25]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)c(F)c12

Procedure:
Analogously to the process described in Example 126, 60 mg (0.195 mmol) of the compound of Example 83A and 53 mg (0.195 mmol) of the compound of Example 23A gave 61 mg (55% of theory) of the title compound. The product obtained from the preparative HPLC purification was dissolved in a little methanol and passed through a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After concentration of the eluate, the residue was dried under high vacuum.