Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([N:32]([CH2:40][CH3:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[CH3:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:40]([N:32]([CH2:30][CH3:31])[C:33]1[CH:34]=[C:35]([NH:39][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:10]=2)[CH:36]=[CH:37][CH:38]=1)[CH3:41]
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCN(CC)c1cccc(N)c1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1cccc(NC(=O)c2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1.05 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), N,N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by chromatography on silica gel, eluent 2% methanol in dichloromethane and crystallised from acetone to give the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 1.07 (t, 6H); 2.31 (s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36 (d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:10]([F:21])[CH:9]=1)=[O:6].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:17][CH:16]=2)=[C:10]([F:21])[CH:9]=1)=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Nc1ccc(Oc2ccccc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension consisting of 3,4-dichloro-3′-fluoro-4′-phenoxybenzanilide (5.05 g, 13.4 mmol) and succinic anhydride (1.48 g, 14.8 mmol) in 1,2-dichloroethane (25 mL) was added aluminum chloride (6.26 g, 47.0 mmol) under ice cooling, and the resulting mixture was stirred at the same temperature for 5 minutes, and then at room temperature for 1.5 hours. The resulting reaction solution was poured into ice water, and the resulting solid was collected by filtration. To the solid was added 50% aqueous acetone (200 mL), and the resulting solution was refluxed for 0.5 hours, then cooled. The obtained solid was collected by filtration, to thereby yield 6.30 g of the title compound.
Reaction SMILES: [O:1]1[CH2:3][C:2]1([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>B(F)(F)F.CCOCC.C1C=CC=CC=1>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[O:1])=[CH:15][CH:14]=1
Reactant: Clc1ccc(C2(c3ccccc3)CO2)cc1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=CC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Borontrifluoride etherate (5 drops) was added to a solution of the crude epoxide (9 0g) in dry benzene (250 ml). After 5 minutes water was added and the benzene layer washed with water until no longer acidic. Evaporation of solvent gave an oil which was chromatographed on silica gel; elution with progressively graded mixtures of light petroleum and ether yielded p-chlorophenyl-phenylacetaldehyde (5 68g 62%9 as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O.O1CCCC1>>[CH:12]1([CH:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[CH2:8][C:9]([OH:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)Cl
Reactant: NC(CC(=O)O)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NC(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Methyl chloroformate (54 uL, 0.70 mmol) was added to a mixture of 3-amino-3-cyclohexylpropanoic acid (100.0 mg, 0.5840 mmol) (Key Organics/Bionet, Cat. #7T-0112) and potassium carbonate (160 mg, 1.2 mmol) in water (2.0 mL, 110 mmol) and tetrahydrofuran (2.0 mL, 25 mmol). After stirring at r.t. for 10 min, the mixture was extracted with ether to remove impurity. The aqueous layer was adjusted to pH=2 with HCl, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (130 mg, 97%). Analytic LCMS (M+H)+: m/z=230.1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[OH:22])[CH:17]=O.C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[CH:17][C:16]3[CH:15]=[C:14]([Br:13])[C:21]([OH:22])=[C:20]([Br:23])[CH:19]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)C2=Cc1cc(Br)c(O)c(Br)c1
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
6-cyano-1,3-dihydro-indol-2-one (46.3 mg, 0.29 mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (80 mg, 0.39 mmol) and p-toluenesulfonic acid monohydrate (1 mg, 0.005 mmol) were treated with toluene (30 mL) and the reaction refluxed with stirring with a Dean-Stark water trap attached for 1.5 h. During this time an orange solid deposited, which, on cooling, was filtered off, washed with toluene and dried in vacuo at 125° C. for 3 days to give 80 mg of 6-cyano-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one; 1H-NMR (DMSO-d6): δ11.05 (bs, 1H), 8.86 (s, 2H), 7.97 (s, 1H), 7.85 (d, J=7.9 Hz, 1 H), 7.50 (d, J=7.9 Hz, 1 H), 7.20 (s, 1H). Mass spectrum (negative ion electrospray): m/z=417 (M−1, 48%), 419 (M−1, 100%), 421 (M−1, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.[OH-].[Na+].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: Nc1cccc(O)c1
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CO[Si](CCCOc1cccc(N)c1)(OC)OC
Yield: 85 %

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 300 g (2.75 mole) m-aminophenol, 560 cc dimethylsulfoxide, 600 cc toluene and 216 cc of a 50% aqueous solution of sodium hydroxide (2.70 moles NaOH). The water present in the reactor was removed by azeotropic distillation under a nitrogen atmosphere at a temperature of 120° C. The temperature of the reaction mixture was then lowered to 90° C. and maintained at about this value during the gradual addition of 545 g (2.75 mole) of 3-chloropropyl trimethoxysilane. Following completion of the addition, which required 2 hours, the reaction mixture was heated at the boiling point for 16 hours. The product was recovered and fractionally distilled as described in the preceding example. The fraction boiling from 178° to 180° C. at a pressure of 3 mm of mercury was collected and weighed 630 g (85% yield). The infrared and nuclear magnetic resonance spectra of the distillate confirm the proposed structure ##STR16## A vapor phase chromatogram of the product indicated a purity of greater than 98%.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[C:12]([O:16][CH:17]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([C:28]2[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH:29]=2)[C:23]=1[C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:44]=1)[C:18]([O:20][CH3:21])=[O:19])([CH3:15])([CH3:14])[CH3:13].[BH4-].[Na+]>C(O)C>[C:12]([O:16][CH:17]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([C:28]2[CH2:33][CH2:32][CH2:31][CH:30]([OH:34])[CH:29]=2)[C:23]=1[C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:44]=1)[C:18]([O:20][CH3:21])=[O:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(C2=CC(=O)CCC2)nn1C
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(C2=CC(O)CCC2)nn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Cerium(III) chloride heptahydrate (62 mg, 0.167 mmol) was added to a solution of methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(3-oxocyclohex-1-en-1-yl)-1H-pyrazol-5-yl]acetate (43c) (63 mg, 0.139 mmol) in ethanol (0.46 mL). The reaction mixture was cooled to 0° C. and sodium borohydride (6 mg, 0.167 mmol) was slowly added. After stirring for 1 hour at the same temperature, the reaction was quenched with water (2 mL) and concentrated in vacuo to remove ethanol. The resulting aqueous layer was extracted with ethyl acetate (2×2 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/ethyl acetate 50/50) to provide methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(3-hydroxycyclohex-1-en-1-yl)-1-methyl-1H-pyrazol-5-yl]acetate (43d) (55 mg, 0.121 mmol, 87%) as a mixture of diastereoisomers.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[O:41])=[CH:36][N:35]=4)[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=3)[C:17]=1[CH2:18][O:19]C(=O)C)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].CO.O.O.[OH-].[Li+]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[O:41])=[CH:36][N:35]=4)[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=3)[C:17]=1[CH2:18][OH:19])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCc2cc(C(C)(C)C)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cccc(N3CCc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Acetic acid 2-(6-tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzyl ester (0.472 mmol) was taken up in THF (7 mL) and methanol (3 mL) and water (5 mL) and then added lithium hydroxide monohydrate (40 mg, 2 eq). The resulting mixture was stirred at room temperature overnight. The next morning the reaction was complete by TLC and most of the THF and methanol was removed under reduced pressure at 55° C. Then ethyl acetate (75 mL) and water (30 mL) were added and the layers were partitioned and then separated. Next, the ethyl acetate layer was washed with water (2×30 mL), brine (1×30 mL) and then dried over magnesium sulfate, filtered and concentrated to give 286 mg of crude product. Preparative Thin Layer Chromatography purification eluting on two 20×40 cm 1000 μM plates in 6% methanol in dicholomethane afforded the title compound (99 mg) as a white powder ((M+H)+=622).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[C:10]([F:30])=[C:11]([N:15]([CH2:27][O:28][CH3:29])[S:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)=O>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[C:10]([F:30])=[C:11]([N:15]([CH2:27][O:28][CH3:29])[S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:4]=1
Reactant: NC(N)=S
Reactant: COCN(c1cccc(C(=O)CBr)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: CCO
Product: COCN(c1cccc(-c2csc(N)n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 60 °C
Yield: 79.3 %

Procedure:
21 mg (0.27 mmol) of thiourea were added to a solution of 122 mg (0.27 mmol) of N-[3-(bromoacetyl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 5 mL of ethanol. The mixture was heated at 60° C. for 20 min in a microwave apparatus. The solvent was then removed, the residue taken up with DCM and washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography eluted with DCM-CH3OH 95/5, giving 92 mg (80%) of the title compound.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[CH:13]=1.C(N1CCNCC1)CC1C=CC=CC=1.[CH2:36]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([CH:43]1[CH2:48][CH2:47][N:46]([C:12]2[CH:13]=[C:14]([F:21])[C:15]([O:19][CH3:20])=[CH:16][C:17]=2[F:18])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1cc(F)c(Br)cc1F
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: COc1cc(F)c(N2CCC(Cc3ccccc3)CC2)cc1F

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene was replaced with 4-bromo-2,5-difluoroanisole (446 mg), and 1-phenethylpiperazine was replaced with 4-benzylpiperidine (2.30 mL). The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=4:1) to provide 4-benzyl-1-(2,5-difluoro-4-methoxyphenyl)piperidine (304 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[OH:29])[C:9]2=[O:37])=[CH:4][CH:3]=1.[CH3:38][NH:39][CH2:40][CH:41]([OH:50])[CH:42]([OH:49])[CH:43]([OH:48])[CH:44]([OH:47])[CH2:45][OH:46]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:39]([CH3:38])[CH2:40][CH:41]([OH:50])[CH:42]([OH:49])[CH:43]([OH:48])[CH:44]([OH:47])[CH2:45][OH:46])=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[OH:29])[C:9]2=[O:37])=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Solvent: CN(C)C=O
Product: CN(CCCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
136 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(6-iodohexyloxy)phenyl]azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 172 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2.5 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C37H48F2N2O8 (686) MS (ESI): M+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>N1C=CC=CC=1>[C:24]1([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:34](=[O:41])[C:35]5[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1)c1cccnc1
Yield: 37.4 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-phenyl-amine (40 mg, 0.105 mmol) in mixture of DCM (1.2 mL) and pyridine (0.3 mL) was added nicotinoyl chloride hydrochloride (23 mg, 0.11 mmol). The resultant mixture was stirred at rt for 12 h. The resultant precipitate was collected by filtration, and washed with water and diethyl ether to give N-{3-[3-(2-phenylamino-pyrimidin-4-yl)-pyrazolo[1,5-a]pyridin-2-yl]-phenyl}-nicotinamide (19 mg). 1H NMR (400 MHz, DMSO-d6) δ 6.56 (m, 1H), 6.95 (m, 1H), 7.15 (m, 1H), 7.27 (m, 2H), 7.36 (m, 1H), 7.51 (m, 2H), 7.62 (m, 1H), 7.71 (m, 2H), 7.96 (m, 1H), 8.11 (m, 1H), 8.17 (m, 1H), 8.35 (m, 1H), 8.50 (m, 1H), 8.79 (m, 1H), 8.86 (m, 1H), 9.13 (m, 1H), 9.64 (s, 1H), 10.6 (s, 1H). LC/MS: m/z 484 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:11]2[N:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH3:47])=[O:45])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[O:23])[CH:7]=1
Reactant: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)cn1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-5-(piperazin-1-yl)picolinamide 49-6 (64 mg, 0.14 mmol) and DIEA (0.07 mL, 0.42 mmol) in THF (1 mL) was added methyl chloroformate (13 uL, 0.17 mmol) dropwise at room temperature. The mixture was stirred for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give methyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 93 as a white powder. MS m/z 519.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.28 (t, 1H, J=6.4 Hz), 8.92 (d, 1H, J=5.2 Hz), 8.62 (m, 1H), 8.32 (m, 2H), 8.20 (d, 1H, J=5.2 Hz), 7.88-7.82 (m, 2H), 7.43 (dd, 1H, J1=7.0 Hz, J2=3.2 Hz), 4.59 (d, 2H, J=6.4 Hz), 3.73 (s, 3H), 3.54-3.51 (m, 4H), 3.37-3.35 (m, 4H).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](S(C)=O)=[N:14][N:15]=[C:3]12.[CH3:19][O-:20].[Na+]>>[CH3:19][O:20][C:13]1[N:4]2[C:3]([C:2](=[CH2:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH:6]=[CH:5]2)=[N:15][N:14]=1
Reactant: C=C1c2ccccc2C=Cn2c1nnc2S(C)=O
Reactant: C[O-]
Agent: [Na+]
Product: C=C1c2ccccc2C=Cn2c(OC)nnc21

Procedure:
The reaction of 11-methylene-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3-methoxy-11-methylene-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from ethyl acetate), melting point: 160°-161° C.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13](O)([CH3:15])[CH3:14])/[C:7](=[N:17]/[C:18](=[O:28])[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:35])CC>C(Cl)Cl>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13]([F:35])([CH3:15])[CH3:14])/[C:7](=[N:17]/[C:18](=[O:28])[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CCCC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CCCC(C)(C)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
The product from Example 80 (50 mg, 0.12 mmol) in CH2Cl2 (4 mL) was treated with DAST (38 mg, 0.24 mmol) at −78° C. The mixture was stirred at −78° C. for 1.5 hrs, quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 29 mg (58%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (d, J=21.48 Hz, 6 H) 1.65 (s, 9 H) 1.68-1.80 (m, 2 H) 1.81-1.93 (m, 2 H) 2.84 (t, J=7.67 Hz, 2 H) 3.91 (s, 3 H) 6.91 (d, J=8.90 Hz, 1 H) 7.33 (dd, J=8.59, 2.76 Hz, 1 H) 7.97 (s, 1 H) 8.11 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 427 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1ccc(CCCN2CCCC2)cc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(Nc2ccc(CCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of 5-nitro-pyrimidin-2-ylamine (0.15 g, 1.1 mmol), intermediate 51 (Example 101) (0.30 g, 1.1 mmol), Pd2(dba)2 (75 mg, 0.082 mmol), Xantphos (96 mg, 0.17 mmol) and cesium carbonate (0.69 g, 2.1 mmol) was suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 15 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10% MeOH/DCM to 20% MeOH and 2% TEA/DCM) to afford the title compound as a yellow solid (0.20 g, 56%).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]([OH:5])=[O:4].BrCC(C)CC.NC(C[C@@H](C)CC)C(O)=O>CO.O>[CH3:9][CH2:8][CH:7]([CH2:6][C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[CH3:10]
Reactant: CCC(C)CC(N)C(=O)O
Agent: CCC(C)CBr
Agent: CC[C@H](C)CC(N)C(=O)O
Solvent: O
Solvent: CO
Product: CCC(C)C[C@H](N)C(=O)O

Procedure:
Two, 2-amino-4-methylhexanoic acid (homoisoleucine, Hil) units were identified after analyzing the PS (phase sensitive) DQF COSY and TOCSY spectra of vitilevuamide. The stereochemistry of the amino acids was confirmed by chemical synthesis of all four diastereomers, and evaluation of the 1-fluoro-2,4-dinitrophenyl-5-L-alanineamide (FDAA; Sigma Chemical Co., St. Louis, Mo.) derived amino acids by HPLC on a cyano column. The mixtures of (2RS,4S) and all four isomers of Hil were synthesized starting from S-(+) and (±)-1-bromo-2-methyl butane (Sigma Chemical Co. or Aldrich Chemical Co., Milwaukee, Wis.) respectively using the method of H. Han & R. A. Pascal, 55 J. Org. Chem. 5173 (1990). The diastereomeric mixture of (2RS,4S)-2-amino-4-methyl hexanoic acid was treated with catalase and L-amino acid oxidase (Aldrich Chemical Co.) at pH 8 for 12-18 hours. Upon acidification and reverse phase chromatography (9:1, MeOH/H2O), the pure (2R,4S) isomer of Hil was isolated. Using these standards it was possible to verify the stereochemistry of the two Hil residues in vitilevuamide by FDAA derivatization and cyano HPLC chromatography (MeOH/1% Acetic acid, 25:75-90:10 at 1 mL/min) with UV detection at 340 nm.