Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N12CCCN=C1CCCCC2>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:10]=[C:9]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12)C(F)(F)F
Temperature: 0 °C
Yield: 40 %

Procedure:
Crude N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide was suspended in dichloromethane (25 mL) and treated with trityl chloride (0.72 g, 2.58 mmol) under stirring. The suspension was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL, 2.78 mmol) was added, producing immediate solubilization. After stirring at 0° C. for 3 hours the reaction mixture was poured into 50 mL of ice containing 1N HCl (5 mL) and extracted with dichloromethane. The organic layer was washed with NaHCO3, brine, dried and concentrated to a crude material that was purified by flash chromatography (eluant: DCM). The desired product was obtained as a white solid (450 mg, yield 40% over two steps)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CCCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]=2)[CH3:10])=[N:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CCOCC3)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Temperature: 140 °C

Procedure:
A mixture of 6-chloro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 37; 174 mg, 0.5 mmol), morpholine (0.8 ml) and DIEA (0.13 ml) in n-BuOH (3 ml) was heated to 140° C. for 4 hrs. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% acetonitrile/H2O, 15 min) to give the title compound as solid (103 mg). 1H NMR: 11.09 (s, 1H), 9.21 (s, 1H), 8.36-8.66 (m, 1H), 7.74 (ddd, 1H), 7.55 (dd, 1H), 5.80-5.84 (m, 1H), 5.73 (s, 1H), 5.01-5.21 (m, 1H), 3.10-3.81 (m, 8H), 2.24 (s, 3H), 1.50 (d, 3H); m/z 399.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]#[N:28])[C:24]([N:29]4[CH2:33][CH2:32][C@H:31]([F:34])[CH2:30]4)=[CH:23][CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)(C)(C)C>Cl.CC#N>[F:34][C@H:31]1[CH2:32][CH2:33][N:29]([C:24]2[C:25]([C:27]#[N:28])=[N:26][C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:11]4[CH:12]=[N:13][C:8]([CH2:7][OH:6])=[CH:9][CH:10]=4)[N:20]=3)=[CH:22][CH:23]=2)[CH2:30]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(Nc2nccc(-c3ccc(N4CC[C@H](F)C4)c(C#N)n3)n2)cn1
Agent: Cl
Solvent: CC#N
Product: N#Cc1nc(-c2ccnc(Nc3ccc(CO)nc3)n2)ccc1N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
Compound 80 (252 mg, 0.5 mmol) was dissolved in 1:1 2 M HCl-MeCN and the reaction mixture stirred at rt for 5 hours. The solvent was removed in vacuo and the residue triturated with 9:1 EtOAc-MeOH to afford the title compound (152 mg, 79%) as a dark yellow solid; LCMS, Rt=2.40 min (MeOH-FA method), m/z 392 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.C(OC(=O)C)(=[O:28])C.[Na].[Na].[C:35]([C:37]1[C:41](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[NH:40][C:39](=[O:47])[C:38]=1O)#[N:36].O=P(Cl)(Cl)Cl>CN(C)C=O>[C:35]([C:37]1[C:41](=[C:42]([C:43]#[N:44])[C:45]#[N:46])[NH:40][C:39](=[O:47])[C:38]=1[C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([O:4][CH3:1])=[O:28])=[CH:13][CH:14]=1)#[N:36]
Reactant: N#CC(C#N)=C1NC(=O)C(O)=C1C#N
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC(CC)CN(CCCCCC(=O)OC)c1ccc(C2=C(C#N)C(=C(C#N)C#N)NC2=O)cc1
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
In a three-neck flask 6-((2-ethylhexyl)(phenyl)amino)hexyl acetate (7.0 g, 0.020 mol) was added to dimethylformamide (100 ml), stirred, and then added with acetic anhydride (2.9 g, 0.028 mol) and 4-cyano-5-dicyanomethylene-3-hydroxy-2-oxo-3-pyrroline disodium salt (5.6 g, 0.024 mol). The temperature was decreased to 0° C., POCl3 was slowly added thereto for 30 min, and then the mixture was allowed to react at room temperature for 6 hours with stirring. A solid product was precipitated with water, filtered, and then dried, thus obtaining 4.0 g of a dark blue solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:28](O)=[O:29])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[N:18]=[CH:19][CH:20]=[CH:21]3)=[O:29])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CN(C(=O)c2cccc3cccnc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A, except using 1-tert-butoxycarbonyl-2(S)-n-butyl-piperazine (0.261 g, 1.078 mmol), 8-quinoline carboxylic acid (0.187 g, 1.078 mmol), EDC.HCl (0.217 g, 1.13 mmol), HOBT (0.157g, 1.02 mmol) in DMF at pH 7 (adjusted with triethylamine). The crude product was chromatographed on silica gel with 5% methanol in chloroform. The title compound was obtained as an oil (0.253 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1>CS(C)=O>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][CH2:19][CH:16]2[CH2:18][CH2:17]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc(CCO)cc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOc1ccc(CCOCC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a flask charged with redistilled dimethylsulphoxide (50 ml) and sodium hydride (50% dispersion, 4.8 g) was slowly added 2-(4-allyloxyphenyl)ethanol (17.8 g) at ice-bath temperature. Cyclopropylmethyl bromide (13.5 g) in dry dimethyl sulphoxide (20 ml) was added with cooling under nitrogen. The reaction mixture was stirred at room temperature overnight, poured on to ice-water and extracted into diethyl ether. The organic layer was thoroughly washed with saturated brine, evaporated under reduced pressure and chromatographed on silica using petroleum ether (40°-60°) as an eluant to afford 1-allyloxy-4-[2-(cyclopropylmethoxy)ethyl]benzene (9 g).
Reaction SMILES: N#N.C(OC([NH:10][C@@H:11]([C:16]([N:18]([CH3:28])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=O)(C)(C)C.CCOCC>C(OCC)(=O)C.Cl>[CH3:28][N:18]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16](=[O:17])[C@@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH2:10]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)CCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSCC[C@@H](N)C(=O)N(C)CCCc1ccccc1
Yield: 112.3 %

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N-methyl-N-(3-phenylpropyl)-D-methioninamide (4.06 g.) in hydrogen chloride-ethyl acetate (3.9 N, 20 ml.) was stirred at room temperature for 40 minutes. Ether (100 ml.) was added, precipitating an oil, and the mixture was stripped of volatiles under vacuum, affording N-methyl-N-(3-phenylpropyl)-D-methioninamide (3.13 g.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1SC)#[N:2].O[O:18][S:19]([O-:21])=O.[K+].[CH3:23]N(C)C=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[S:6][C:7]=1[S:19]([CH3:23])(=[O:21])=[O:18])#[N:2]
Reactant: CSc1sc(C(=O)OC(C)(C)C)cc1C#N
Reactant: CN(C)C=O
Reactant: O=S([O-])OO
Agent: [K+]
Product: CC(C)(C)OC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 4-cyano-5-(methylthio)thiophene-2-carboxylate (1.4 g, 5.5 mmol) and oxone (14.4 g, 21.5 mmol) in dimethylformamide (100 mL) was stirred at room temperature for 16 hours. The reaction mixture was then poured into ice/water (400 mL) and extracted with ethyl acetate. Organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to afford 1.5 g of the title compound. LC-MS: Rt 6.2; [M+H]+ 288.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:29][O:30][C:31]([C:33]1[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=1[NH:35][C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:32]>CN(C)C=O>[CH3:29][O:30][C:31]([C:33]1[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=1[NH:35][C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:40][CH2:39]1)=[O:32]
Reactant: COC(=O)c1ccccc1NC(=O)CN1CCNCC1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1

Procedure:
3.3 Grams of 3,4-dimethoxybenzoic acid was dissolved in 30 ml of dimethylformamide, then 2.4 g of triethylamine was added to this solution. Under ice-cooled condition, to this solution was added dropwise 2.75 g of isobutyl chloroformate with stirring, and further stirred for 30 minutes. Then to this reaction mixture was added dropwise a DMF solution containing 5.8 g of o-methoxycarbonyl-α-(1-piperazinyl)acetanilide and stirred for 5 hours. The reaction mixture was concentrated to dryness and subjected to extraction by adding chloroform and 1 N-sodium hydroxide. The chloroform layer was washed with water, dried and removed by distillation, the residue obtained was crystallized by adding ethyl acetate and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 2.3 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>CCOC(C)=O>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:8]2[C:7](=[O:37])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1

Procedure:
A solution of tert-butyl (1S,2R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (2.4 g, 4.04 mmol) and TFA (5 mL, 64.9 mmol) was stirred at 80° C. for 30 min. The resulting suspension was diluted with EtOAc (5 mL) and filtered. The filtrate was evaporated in vacuo. The residue was diluted with H2O (300 mL) and EtOAc (100 mL) and filtered. The precipitate was washed with EtOAc and dried to give the title compound as a TFA salt (900 mg). The filtrate was extracted with EtOAc (200 mL). The aqueous phase was neutralized with saturated aq NaHCO3 solution and extracted with EtOAc (2×400 mL) and THF (2×200 mL). The organic phases were combined, dried over MgSO4, and evaporated. The residue was washed with EtOAc to give a first crop (400 mg) of the title compound as the free base. The TFA salt obtained above was diluted with saturated aq NaHCO3 solution (20 mL) and stirred at RT overnight. The resulting suspension was filtered and the solids were washed with EtOAc to give a second crop (700 mg) of the title compound as the free base (1.1 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:7]([CH2:8][CH3:9])[C:6]([CH:10]=[C:11]3[N:37]=[C:14]([CH:15]=[C:16]4[NH:32][C:19](=[C:20]([CH2:30][CH3:31])[C:21]5[C:22]([CH2:28][CH3:29])=[C:23]([CH2:26][CH3:27])[C:24]=1[N:25]=5)[C:18]([CH2:33][CH3:34])=[C:17]4[CH2:35][CH3:36])[CH:13]=[CH:12]3)=[C:5]([CH2:38][CH3:39])[C:4]=2[CH2:40][CH3:41].[Pt:42](Cl)Cl>CN(C)C=O>[Br:1][C:2]1[C:3]2[N:7]([CH2:8][CH3:9])[C:6]([CH:10]=[C:11]3[N:37]=[C:14]([CH:15]=[C:16]4[NH:32][C:19](=[C:20]([CH2:30][CH3:31])[C:21]5[C:22]([CH2:28][CH3:29])=[C:23]([CH2:26][CH3:27])[C:24]=1[N:25]=5)[C:18]([CH2:33][CH3:34])=[C:17]4[CH2:35][CH3:36])[CH:13]=[CH:12]3)=[C:5]([CH2:38][CH3:39])[C:4]=2[CH2:40][CH3:41].[Pt:42]
Reactant: Cl[Pt]Cl
Agent: CCC1=C(CC)c2nc1c(CC)c1[nH]c(cc3nc(cc4c(CC)c(CC)c(c2Br)n4CC)C=C3)c(CC)c1CC
Solvent: CN(C)C=O
Product: [Pt]

Procedure:
In a suitable 150 ml vessel 50 ml of dimethylformamide is brought to reflux and 20 mg 5-bromo octaethylporphine free base is added and dissolved. To this solution 8 mg platinum chloride is added and permitted to react for about 20 minutes. Thereafter, the reaction mixture is permitted to cool and crystal formation promoted by the addition of 50 ml distilled water. The reaction mixture is allowed to sit for about twenty four hours to increase crystal size. The reaction mixture is filtered by vacuum filtration and the solids retained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[CH:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: Brc1cccc(-n2cncn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4cncn4)c3)cnc2n1

Procedure:
1-(3-Bromophenyl)-1H-[1,2,4]triazole (1.7 g, 7.6 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (3.8 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (1-3%), then crystallisation from toluene/isohexane, gave 3-[3-([1,2,4]triazol-1-yl)-phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine as an off-white solid: δH (400 MHz, DMSO) 9.43 (1H, d, J 7), 9.41 (1H, s), 8.38 (1H, s), 8.30 (1H, s), 8.26-8.28 (1H, m), 7.97-8.00 (1H, m), 7.76-7.81 (2H, m), 7.56 (1H, d, J 7); m/z (ES+) 331 (M++H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[CH3:10])=[N+]=[N-].[C:11]1(=[O:15])[CH2:14][CH2:13][CH2:12]1>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH3:10][C@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[N:1]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]
Reactant: C[C@H]1CCCC[C@H]1N=[N+]=[N-]
Reactant: O=C1CCC1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H]1CCCC[C@H]1N1CCCC1=O
Temperature: 0 °C
Yield: 36.3 %

Procedure:
Dissolve cis-1-azido-2-methyl-cyclohexane (Preparation 31) (3.68 g, 26.41 mmol) and cyclobutanone (1.85 g, 26.41 mmol) in dichloromethane (200 mL). Cool the solution to 0° C. and add titanium chloride (15.03 g, 79.23 mmol) under nitrogen. Stir the reaction for 24 hours at room temperature. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc/Hexane) to give 1.74 g (36%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][C:10]=3[C:9]([CH2:15][OH:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.N1C=CC=C[C:23]=1C1C=CC=CN=1.BrC[C:36]([O:38]CC)=[O:37].[OH-].[Na+]>C1COCC1.CO>[C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][C:10]=3[C:9]([CH:15]([O:16][CH3:23])[C:36]([OH:38])=[O:37])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1nn(-c2ccccc2)c2c1CCC2
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2ccccn2)nc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(C(=O)O)c1nn(-c2ccccc2)c2c1CCC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-phenyl-1,4,5,6-tetrahydro-3-cyclopentapyrazolemethanol (2.14 g, 10 mmol) in THF (40 ml) was cooled to -10° C. and treated with 1.6M n-butyl lithium (6.2 ml, 10 mmol) using bipyridyl indicator. After 20 minutes, ethyl bromoacetate (1.9 g, 1.26 ml, 11.4 mmol) was added, reached at -20° C. for 45 minutes, then at ambient temperature for 18 hours. The solution was poured into ice water, acidified, and the products extracted into ethyl acetate. Drying and evaporation of solvent gave a residue containing unreacted methanol starting material. The residue was soaponified in methanol (150 ml) with 2N sodium hydroxide (25 ml) for 2 hours. The solution was concentrated to 50 ml, diluted to 300 ml with water, and neutral products extracted into ethyl acetate. The alkaline solution was acidified and extracted with ethyl acetate to yield crude title compound. Purification on CC-4 silica gel (100 g) with 1:1 ethyl acetate-Skelly B eluent gave pure title compound. Crystallization from ethyl acetate provided title compound (0.50 g), m.p. 106°-107° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][C@H:11]1[C:16]2[C:17]([CH3:23])=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=2[CH2:14][C@@H:13]([CH2:24][N:25]=[N+]=[N-])[O:12]1)=[N+]=[N-]>C(OCC)C>[NH2:7][CH2:10][C@H:11]1[C:16]2[C:17]([CH3:23])=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=2[CH2:14][C@@H:13]([CH2:24][NH2:25])[O:12]1
Reactant: COc1ccc(C)c2c1C[C@@H](CN=[N+]=[N-])O[C@H]2CN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C)c2c1C[C@@H](CN)O[C@H]2CN
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Lithium aluminum hydride (2.4 mL of a 1.0 M solution in diethyl ether, 2.4 mmol) is added dropwise to a solution of [1R,3S] 1,3-bis(azidomethyl)-3,4-dihydro-5-methoxy-8-methyl-1H-2-benzopyran (283 mg, 1.2 mmol), from Step 5, in 10 mL of anhydrous diethyl ether at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 45 min. The reaction is then quenched by the sequential addition of 91 μL of water, 91 μL of 15% aqueous sodium hydroxide solution and 273 μL of water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>O=S(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
The product of Step 1 (6.4 g, 0.026 mol) was heated in SOCl2 (30 mL) at reflux for 2 h. The excess reagent was then evaporated and chased with toluene (2×10 mL). The residue was dissolved in dry CH2Cl2 (20 mL) and added dropwise to a solution of 4-(dimethylamino)pyridine (3.2 g, 0.026 mol) and 4-aminobenzotrifluoride (4.3 g, 0.026 mol) in CH2Cl2 (40 mL) cooled in ice. When addition was complete (10 min), the mixture was stirred and warmed to room temperature over 1 h, then washed with 2N HCl (15 mL), 2N Na2CO3 solution (15 mL), brine (10 mL), dried (MgSO4) and concentrated to give 8.4 g (84% yield) of product as a buff solid. 1H NMR (360 MHz, CDCl3): 7.40 (1H, d, J 1.4 Hz), 7.44 (1H, dd, J 1.4 and 8.5 Hz), 7.63 (2H, d, J8.5 Hz), 7.80 (2H, d, J 8.5 Hz), 8.14 (1H, d, J 8.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:62][N:63]([CH3:69])[CH:64]1[CH2:68][CH2:67][NH:66][CH2:65]1>CN(C=O)C.C(#N)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:66]1[CH2:67][CH2:68][CH:64]([N:63]([CH3:69])[CH3:62])[CH2:65]1)=[O:6]
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Reactant: CN(C)C1CCNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(N)c(C(=O)N4CCC(N(C)C)C4)c3)cc12
Yield: 9.1 %

Procedure:
25 mg (66 μmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid and 72 mg (0.14 mmol) of (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate were dissolved in a mixture of 200 μL of DMF and 1 mL of acetonitrile. 100 μL (approx. 0.88 mmol, density unknown) of 3-(dimethylamino)pyrrolidine was added and the resulting mixture was irradiated in a Personal Chemistry® Optimizer to 100° C. for 30 min. The resulting mixtures was evaporated and the residue purified by flash chromatography on amine functionalized silica gel (Teledyne ISCO Inc.) using a gradient of ethyl acetate containing 15% of methanol in hexanes. The resulting material was then purified by mass-triggered reverse-phase HPLC to afford 2.9 mg (6 μmol, 10%) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-di-methylamino-pyrrolidin-1-yl)-methanone as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, 1H), 8.24 (s, br., 1H), 7.64 (dd, 1H), 7.55 (d(m), 1H), 7.46 (ddd, 1H), 7.38 (m, br., 1H), 7.21 (d, 1H), 7.09 (ddd, 1H), 5.45 (m, br., 2H), 3.83 (s, 3H), 3.75 (m, br. 1H), 3.64 (m, br. 1H), 3.47 (m, br. 1H), 3.24 (m, br. 1H), 2.18 (s, br. 3H), 2.09 (s, br. 3H), 2.01 (m, br. 1H), 1.80-1.65 (m, 2H), MS: m/z 475.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH:27]1([NH:31][C:32]2[NH:36][C:35]([CH3:37])=[N:34][N:33]=2)[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:31]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:33]3[N:34]=[C:35]([CH3:37])[N:36]=[C:32]23)[CH2:28][CH2:29][CH2:30]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1nnc(NC2CCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.8 g) and N-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-amine (0.4 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 52%).