Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Product: C[C@H](O)c1ccccc1Cl

Procedure:
(S)-1-(2-Chloro-phenyl)-ethanol was prepared as described in Example 35, Step 1 using 2′-chloroacetophenone and (R)-(+)-2-methyl-CBS-oxazaborolidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[Cl:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>Cl.O1CCOCC1>[ClH:15].[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[N:1]1[CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A sealed tube reactor was mixed with tert-butyl piperidin-4-ylcarbamate (1.0 g, 5.0 mmol) and 2-chlorobenzoxazole (2.3 g, 15.0 mmol). The reactor was sealed and the tube was heated while stirring at a temperature of 100° C. for 2.0 hours. The tube was cooled to RT and the resulting oily solid was dissolved in 4.0 N HCl in 1,4 dioxane (25 mL). The reaction stirred over 16.0 hours and was concentrated to dryness. The resulting solid was triturated with ether and filtered. The product was washed with ether and dried to give 1.1 g of crude solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[CH2:16][OH:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:3]=1[C:31]([NH2:33])=[O:32]>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[CH:16]=[O:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:3]=1[C:31]([NH2:33])=[O:32]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2CO)c1N
Agent: O=[Mn]=O
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2C=O)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of 5-amino-1-(2-(hydroxymethyl)-5-nitrophenyl)-3-(4-phenoxy phenyl)-1H-pyrazole-4-carboxamide (550 mg, 1.24 mmol) in 20 mL of DCM was added MnO2 (500 mg, 5.75 mmol). After stirring at RT for 16 hr, the mixture was filtered. The filtrate was concentrated to afford 400 mg (73%) of 5-amino-1-(2-formyl-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide as a yellow solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].C1(=O)O[CH2:12][CH2:11][O:10]1>>[OH:10][CH2:11][CH2:12][O:7][C:1](=[O:8])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: O=C1OCCO1
Reactant: CC/C=C/CC(=O)O
Product: CCC=CCC(=O)OCCO

Procedure:
For instance, we treated trans-3-hexenoic acid (a low molar mass model compound for HTBN) with ethylene carbonate in the presence of a phase transfer catalyst to yield 2-hydroxyethyl-3-hexenoate. More specifically, trans-3-hexenoic acid (about 1.14 grams; about 0.001 moles, commercially available from Aldrich Chemical Co., Milwaukee, Wis.), ethylene carbonate (about 0.97 grams; about 0.001 moles) and phase transfer catalyst were added to a 25 ml reaction flask containing a magnetic stirrer. The mixture was stirred at elevated temperature conditions to effect the hydroxyethylation reaction of the hexenoic acid. The reaction yields were estimated from the 1H NMR spectrum of the crude product mixture.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.[Li+].[Cl-].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:51])[CH3:50])=[N:46][CH:47]=2)O1.O>O1CCOCC1>[Cl:31][C:29]1[CH:28]=[CH:27][C:4]2[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=[C:2]([C:42]3[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:51])[CH3:50])=[N:46][CH:47]=3)[C:3]=2[CH:30]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(NC(C)=O)nc3)c3cc(Cl)ccc32)cc1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (208 mg, 0.439 mmol), LiCl (56 mg, 1.32 mmol), and CsOH (221 mg, 1.32 mmol) were combined, then a solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (115 mg, 0.439 mmol) in 1,4-dioxane (3 mL) was added followed by water (300 uL). The mixture was purged with nitrogen, then tetrakis(triphenylphosphinepalladium(0) (51 mg, 0.044 mmol) was added and the flask was lowered into a 100° C. oil bath and heated at 100° C. for 3 h. The mixture was allowed to cool, then diluted with ethyl acetate and rinsed with water 2× then brine and dried (MgSO4). Chromatography eluting with 40-50% ethyl acetate in hexanes to give a colorless oil (210 mg, 83% yield). MS (ES+) m/z 573.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:7]2=[O:12].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CC(OC(C)=O)=O>[Br:20][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:7]2=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1C(=O)C=C(SC(C)C(=O)O)C2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)OC(C)=O
Product: CC(SC1=CC(=O)c2c(CBr)cccc2C1=O)C(=O)O
Reaction time: 0.5 h

Procedure:
The acid 1 (59 mmol), N-bromosuccinimide (59 mmol), and azobis (2-methyl-propionitrile) (0.5 g, 3 mmol) is combined in 200 mL of Ac2O and stirred at 120°-130° C. for about 0.5 hours. When the color lightens, the solution is poured onto ice. The yellow solid is collected and dissolved in CHCl3. The CHCl3 solution is dried using Na2SO4, concentrated to a small volume, and chromatographed on silica gel column (benzene) to yield the brominated acid (5-bromomethyl-1,4-naphthoquinonyl thio)-proprionic acid, designated as compound 1b.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH:29]=O)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:22]=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc2cc[nH]c12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5cc[nH]c45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-7-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-7-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: Fc1ccc2c(c1)ncn2C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccc2c(c1)ncn2C1CCNCC1
Yield: 109.4 %

Procedure:
The title compound was prepared from 120 mg of 1-(1-benzyl-piperidin-4-yl)-5-fluoro-1-H-benzoimidazole (from Step B), 120 mg of 10% palladium on carbon and 120 mg ammonium formate in 5 mL of MeOH, using a procedure analogous to that described in Example 95, Step C to provide 93 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[N:24]=[C:23]([C:25]([OH:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[N:16]=[N:15][N:14]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([OH:28])([CH3:26])[CH3:27])[N:24]=4)[C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1cccc(CBr)n1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(C(C)(C)O)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine and 2-(6-bromomethylpyridine-2-yl)propan-2-ol by the alkylation method described in Example 36.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C1(N[C:13]([C:15]2[C:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:14])C=CC=CC=1.O>ClC1C=CC=CC=1>[Cl:29][C:25]1[CH:26]=[CH:27][C:28]2[C:13](=[O:14])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[CH2:21][CH2:22][C:23]=2[CH:24]=1
Reactant: O=C(Nc1ccccc1)c1ncccc1CCc1cccc(Cl)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C1c2ccc(Cl)cc2CCc2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of trifluroromethanesulfonic acid (63.2 ml; 0.71 mol) and phosphorus oxychloride (66.4 ml; 0.71 mol) in chlorobenzene (400 ml) was stirred for ½hour at room temperature. A solution of N-phenyl-3-[2-(3-chlorophenyl)ethyl]-2-pyridine carboxamide 4 (120 g; 0.36 mol) in chlorobenzene (240 ml) was added. The mixture was heated at 110° C. for 18 hours followed by cooling to 50° C. Water (400 ml) was added and the biphasic mixture heated to 80° C. for ½ hour. The mixture was cooled to room temperature, stirred vigorously for 10 minutes, then allowed to stand for 10 minutes. The product was removed by filtration and partitioned between water (300 ml) and toluene (500 ml). The pH of the aqueous phase was adjusted to 10 with 10M NaOH solution. 100 ml of the organic phase was removed by distillation under reduced pressure. Charcoal (5.5 g) was added and the mixture filtered through a pad of celite. The solution was concentrated under vacuum to 300 ml and 150 ml of hexane was added. The mixture was cooled to 0-10° C. for 1 hour with stirring prior to filtration. The product was washed with 100 ml of chilled toluene and then air-dried for several hours. Yield 44.1 g (50.8%)
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:38]>ClCCl>[C:1]([NH:18][C@H:19]([C:27]([F:38])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
FMOC-L-Phenylalanine (17 g, 44 mmol) (Bachem) was dissolved in dichloromethane (100 mL). Pyridine (3.55 mL, 44 mmol) (Aldrich) and cyanuric fluoride (6 g, 44 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 3.5 hours. Ice cold water (300 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford FMOC-L-phenylalanyl fluoride as a white powder. (Yield 13.6 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:6]=1.C(N(CC)CC)C.CN(C)C=O.[S:35](Cl)([CH3:38])(=[O:37])=[O:36]>C(Cl)Cl.O>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:5]3[N:6]=[C:2]([NH:1][S:35]([CH3:38])(=[O:37])=[O:36])[S:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15]1
Reactant: Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1

Procedure:
To a mixture of 2-amino-4-[4-(3-indolyl)piperidinomethyl]thiazole (1.73 g), triethylamine (3.1 ml) and N,N-dimethylformamide (15 ml) was added dropwise a solution of mesyl chloride (0.86 ml) in methylene chloride (1 ml) at 5° to 7° C. with stirring. The mixture was further stirred at that temperature for 2 hours, after which a solution of mesyl chloride (0.34 ml) in methylene chloride (0.5 ml) was added. The reaction mixture was further stirred at the same temperature for 1.5 hours. Following addition of water (50 ml), the reaction mixture was extracted with a mixture of chloroform and methanol (60 ml, 10:1 V/V) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 ml) and, then, 10% aqueous sodium hydroxide solution (20 ml) was added gradually thereto. The mixture was stirred at ambient temperature overnight. The reaction mixture was then adjusted to pH 7.0 with diluted hydrochloric acid and extracted with a mixture of chloroform and methanol (100 ml, 10:1 V/V). The organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel, followed by elution with a mixture of chloroform and methanol (10:1 V/V). The eluate gave 4-[4-(3-indolyl)piperidinomethyl]-2-mesylaminothiazole (480 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([NH:7][C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH:14]=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1Nc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccnc1Nc1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 104.7 %

Procedure:
6.35 g (31.7 mmol) of (2-phenylamino-3-pyridinyl)methanol was dissolved in chloroform (100 mL), and 8.27 g (95.1 mmol) of manganese dioxide was added thereto. The resulting mixture was stirred for 7 hours at 60° C. The reaction mixture was filtered, and the filtrate was concentrated. Thus, 6.58 g of the title compound was obtained as an orange-colored solid (yield: quantitative).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2].[BH4-].[Na+].Cl.[Cl-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(O)C[C@H]1C(=O)O
Reaction time: 6.5 h
Yield: 105.6 %

Procedure:
To a cold (ice bath solution of (1R,2R)-4-Oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester (3.0 g) in tetrahydrofuran (30 mL) was added sodium borohydride (737 mg) in several portions over 5.5 h. After 6.5 h, hydrochloric acid (1N, 40 mL) then sodium chloride (8 g) were added to the reaction mixture. After 30 min, the reaction mixture was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to afford the title compound (3.2 g, 95%) as colorless oil, used in the next step without further purification. MS (EI): 201.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.N#N.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[O:35][CH3:36].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClC(Cl)C.C(O)(C)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: N#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred chilled solution (0° C.) of 2,4-dichloro-5-(trifluromethyl)pyrimidine (0.800 g, 3.68 mmol) under a stream of dry N2 gas in 1:1 dichloroethane/tert-butanol (50 mL) was added a solution of zinc chloride (1 M in diethyl ether; 4.42 mL, 4.42 mmol). After 1 hour of stirring at 0° C., a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (I2) in 1:1 dichloroethane/tert-butanol (15 mL) (1.13 g, 3.68 mmol, 1 eq.) was added drop wise over 30 minutes followed by the drop wise addition of a solution of triethylamine (0.565 mL, 0.410 mmol, 1.1 eq.) in 1:1 dichloroethane/tert-butanol (5 mL) over 30 minutes. The resulting mixture was then stirred vigorously at room temperature for 18 hours. The volatiles were evaporated under reduced pressure and the residue then dried under high vacuum. Ethyl acetate and water were added and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate), filtered and evaporated to give the crude product as a dark yellow foam. The crude product was purified by flash column chromatography on silica gel (0-20% ethyl acetate/petroleum ether) to yield the title compound (I3) (1.25 g, 69%) as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.11 (t, 4H, J=5.2 Hz), 3.59 (t, 4H, J=5.0 Hz), 3.88 (s, 3H), 6.54 (s, 1H), 6.57 (d, 1H, J=9.4 Hz), 7.83 (s, 1H), 8.17 (d, 1H, J=8.5 Hz) and 8.53 (s, 1H). LCMS Method B: rt 9.24 min; m/z 488.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1C=CC=CC=1.[CH3:25][C:26]([N:29]1[C:33]([NH2:34])=[CH:32][C:31]([CH3:35])=[N:30]1)([CH3:28])[CH3:27]>C(O)(=O)C>[CH3:28][C:26]([N:29]1[C:33]2[N:34]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:32]=2[C:31]([CH3:35])=[N:30]1)([CH3:25])[CH3:27]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1c(C)nn2C(C)(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (327 mg, 1.305 mmol), benzene (8 mL), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (200 mg, 1.305 mmol), and acetic acid (2 mL). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 0.41 g (85%) of product. LCMS E-S (M+H)=368.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s, 9 H), 2.55 (s, 3 H), 7.11 (d, J=8.84 Hz, 2 H), 7.89 (s, 1 H), 8.16 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=[O:38]>N1C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH:37]=[O:38])=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)n(Cc3ccccc3)nc12
Reactant: O=Cc1ccccc1O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: O=Cc1ccccc1Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1

Procedure:
The preparation of this compound is was similar to that described for Example 3. 2-Benzyl-3-(3-bromo-phenyl)-7-trifluoromethyl-2H-indazole (60 mg, 0.139 mmol), cesium carbonate (272 mg, 0.835 mmol), CuI (80 mg, 0.417 mmol) and 2-hydroxy-benzaldehyde (51 mg, 0.417 mmol) were dissolved in 6 ml of dry pyridine. The reaction and work-up were carried out as described for Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30]C(=O)OC(C)(C)C)=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.F[C:42](F)(F)[C:43](O)=[O:44].CO>C(Cl)(Cl)Cl>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:15]3[N:16]=[CH:17][C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH3:42])[CH:7]=[CH:6][CH:5]=4)=[CH:9][C:10]=3[N:11]=2)=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a 250 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (1.6 g, 0.0029 mol) and DCM (160 mL) were added and the flask cooled to 0° C. To the reaction flask, trifluoroacetic acid (16 mL, 10% volume) was added at 0° C. and the reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure and methanol was added to provide a solid. The solid was collected by filtration. The solid was suspended into water and basified with saturated sodium bicarbonate solution. The reaction mixture was extracted with chloroform (3×200 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude product. The crude product was subjected to flash column chromatography using 4% methanol in chloroform. The obtained solid was washed with methanol and diethyl ether, filtered and dried under vacuum to afford the title compound as off-white solid (0.900 g, 69%). 1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.22 (s, 2H), 9.02 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.24 (s, 2H), 4.55 (br s, 4H), 3.87 (t, J=4.4 Hz, 4H), 2.12 (s, 3H). LC-MS (ESI): Calculated mass: 442.2; Observed mass [M+H]+: 443.1. (RT=0.18 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)(=[O:23])=[O:22])(=[O:14])=[O:13]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]ncc2c1
Yield: 24.3 %

Procedure:
2-Methylsulfonyl-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 1 g of 5-amino-1H-indazole, 20 ml of pyridine and 1.91 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.64 g of 2-methylsulfonyl-N-(1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a white solid melting at 245° C. (analysis C14H13N3O4S2 % calculated C, 47.85; H, 3.73; N, 11.96; O, 18.21; S, 18.25. % found C, 47.42; H, 3.72; N, 11.64; S, 17.97).