Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(C)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
A mixture of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate (8.0 g, 20.28 mmol) in methylene chloride (60 ml) was cooled to 0° C. and triethylamine (12.69 ml, 91.1 mmol) in methylene chloride (25 ml)was added, followed by the addition of acetyl chloride (4.34 ml, 60.84 mmol). The mixture was stirred at room temperature overnight and diluted with methylene chloride. The mixture was washed with water, 2N citric acid, saturated sodium chloride and then dried with anhydrous sodium sulfate. The solvent was removed in vacuo to give 8.6 g of a yellow oil.
Reaction SMILES: [F:1][C:2]1([C:12](OCC)=[O:13])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1([CH2:12][OH:13])[CH2:3][CH2:4][N:5]([CH:8]2[CH2:9][O:10][CH2:11]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(C2COC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(F)CCN(C2COC2)CC1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 372A (0.59 g) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (1.80 mL) at 0° C. The reaction was removed from the ice bath and allowed to warm to room temperature. The reaction was quenched by the dropwise addition of 0.6 mL of water followed by 0.2 ml of 2N aqueous NaOH. The reaction was filtered through diatomaceous earth and rinsed with ethyl acetate (50 mL). The organics were concentrated and loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 0.75% to 7.5% methanol/dichloromethane over 30 minute (flow=40 mL/minutes) to give the title compound.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C@H:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:7][C:5]([C@H:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: COC(=O)[C@@H](O)[C@@H](CC(C)C)C(=O)O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@H](CC(C)C)[C@H](O)C(=O)OC
Reaction time: 8 h

Procedure:
2.1 ml of allyl bromide were added to a solution of 4.52 g of methyl 3(R)-carboxy-2(S)-hydroxy-5-methylhexanoate and 7.9 g of caesium carbonate in 30 ml of dimethylformamide. The mixture was stirred overnight and then evaporated. The residue was dissolved in dichloromethane and washed with 2M aqueous hydrochloric acid. The dichloromethane phase was then dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetatelhexane (1:9 increasing to 2:8) for the elution. There were obtained 2.88 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-hydroxy-5-methylhexanoate in the form of a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[NH:27][N:26]=[N:25][N:22]=2)=[CH:15][CH:14]=1
Reactant: N#CCCCOc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(OCCCc4nnn[nH]4)cc3)ccc2c1
Yield: 46.2 %

Procedure:
A mixture of 8.0 g of 4-[4-(2-quinolylmethyloxy)phenoxy]butyronitrile, 4.9 g of sodium azide and 4.0 g of ammonium chloride is heated with 25 ml of dry dimethylformamide at 140° C. for 20 hours. The reaction mixture is poured into ice, basified with 1N sodium hydroxide and extracted 2 times with warm ethyl acetate. The aqueous fraction is acidified with acetic acid. The product is filtered and washed with water to give 6.6 g of crude product. Crystallization from ethyl acetate gives 4.2 g of the light tan product, M.P. 158°-160° C.,
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[N:9]1(C(OC(C)(C)C)=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Br:8][C:14]1[CH:13]=[C:12]2[C:17](=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)[NH:9][CH2:10][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.8 %

Procedure:
NBS (51.3 g, 0.29 mol) was added in several portions to a solution of 1-(1,1-dimethylethyl) 7-ethyl 2,3-dihydro-1H-indole-1,7-dicarboxylate (140.3 g, 0.48 mol) in CH2Cl2 (1200 mL) and the reaction mixture was stirred at room temperature overnight. The reaction solution was washed with 2 M NaOH (500 mL) and water (500 mL), and was then dried (Na2SO4). The solution was concentrated in vacuo to 500 mL and TFA (130 mL, 1.69 mol) was added. The mixture was stirred at room temperature overnight. A solution of 2 M NaOH was added to bring the reaction mixture to pH>8. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried (Na2SO4) and the solvent was evaporated, giving 129.1 g (99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:27](=[O:28])[C:11]3=[CH:12][NH:13][C:14]([CH3:26])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24]O)=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Cl-].[Li+].CS([Cl:43])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:27](=[O:28])[C:11]3=[CH:12][NH:13][C:14]([CH3:26])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][Cl:43])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(C#CCO)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(C#CCCl)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.6 %

Procedure:
To a solution of the product of Example 68 (0.6 g, 1.5 mmol), 2,6-lutidine (0.72 ml, 6.2 mmol) and lithium chloride (0.262 g, 6.2 mmol) in N,N-dimethylformamide (6 ml) at 0° C. was added methanesulphonyl chloride (0.36 ml, 4.6 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 7 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give the product as a yellow solid (0.463 g, 74%). 1H NMR (360 MHz, DMSO-d6) δ12.49 (1H, br s), 8.59 (1H, s), 8.13 (2H, d, J 9.0 Hz), 7.59 (4H, m), 7.41 (2H, d, J 9.0 Hz), 4.75 (2H, s), 2.26 (3H, s); MS (ES+) m/z 408/410/412 [MH]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5][N:4]=1.O1CCCC1.B>O1CCCC1>[OH:10][CH2:9][C:6]1[CH:5]=[N:4][C:3]([C:2]([F:13])([F:12])[F:1])=[N:8][CH:7]=1
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Agent: B
Solvent: C1CCOC1
Product: OCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.3 %

Procedure:
To an ice-bath cooled solution of 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (Description 118; 2 g, 10.4 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise borane tetrahydrofuran complex [1.0M solution in THF] (15.6 ml, 15.6 mmol), after complete addition the mixture was stirred at room temperature for 90 mins. The reaction was quenched by the careful addition of water (2 ml), followed by saturated aqueous K2CO3. The organic layer was separated, and the aqueous phase extracted with Et2O. The combined organics were then washed with water, saturated NaCl, dried over Na2SO4, filtered and evaporated to give the title compound (580 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH2:34][F:35])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][F:35])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCCF)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CCF)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.26 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 445 mg (2.27 mmol) of 2-fluoroethyl trifluoromethanesulphonate and 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by column chromatography (120 g silica cartridge, flow rate: 80 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 360 mg (67% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][CH3:23])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: C1COCCO1
Product: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (46.4 g, 152.6 mmoles) in 500 ml of dioxane was added carbonyl diumidazole (25.4 g, 156 mmoles) in a portionwise manner. The resulting mixture was stirred for about 2.5 hours at room temperature and then stirred at 450° C. for 30 minutes. Next, 2-methoxybenzylamine (20.7 ml, 158.7 mmoles) was added and the reaction mixture was then stirred for 16 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[CH3:17][C:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][NH:20][N:19]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:22]4[C:18]([CH3:17])=[N:19][NH:20][CH:21]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 80 °C
Yield: 30.1 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.51 mmol), 3-methylpyrazole-4-boronic acid pinacol ester (117 mg, 0.56 mmol), PdCl2dppf.DCM (42 mg, 0.05 mmol) and Cs2CO3 (416 mg, 1.28 mmol) in dioxane (4 mL) and H2O (1 mL) was purged with argon and heated at 80° C. for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-3% MeOH in DCM) affording 9-Bromo-2-(3-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (53 mg, 30%). LCMS: RT 2.21 min [M+H]+ 345.3
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:19]=O>>[CH2:11]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:1]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCN(C)CCCCCCCC
Reactant: O=O
Product: CCCCCCCCN(C=O)CCCCCCCC
Yield: 4.5 %

Procedure:
By essentially the procedure of Example 1, a tube was charged with 40 g of methyldioctylamine and 1.0 g of CuCl2. 2H2O. The reaction was run at 109°-120° C. for 25 min while oxygen (0.2 mole) was injected incrementally at 160-275 psi. GC/MS analysis showed a 72.0% conversion of methyldioctylamine and a 4.5% yield of dioctylformamide.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:12]=1[NH2:13].[CH2:22]([C:34]1[N:35]=[CH:36][N:37]([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](O)=[O:41])[CH:38]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.ClCCl>[CH2:22]([C:34]1[N:35]=[CH:36][N:37]([CH:39]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:40]([NH:13][C:12]2[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[O:10][CH3:9])=[O:41])[CH:38]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1cn(C(C(=O)O)c2ccccc2)cn1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
Excess triethylamine (2 mL) was added to a suspension of 2,4,6-trimethoxyaniline hydrochloride (1.6 g, 7.3 mmol) in 500 mL THF and stirred for 1 hour before filtering to remove triethylamine hydrochloride. The filtrate was concentrated and redissolved in 500 mL dichloromethane along with (±)-4-dodecyl-α-phenyl-1H-imidazole-1-acetic acid (2.45 g, 6.6 mmol) at 0° C. Dicyclohexylcarbodiimide (1.43 g, 6.9 mmol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Filtered to remove a white solid and partitioned the filtrate between dichloromethane and IN HCl. The organic layer was washed with 1N NaOH, dried over MgSO4, filtered, and concentrated. The resulting residue was chromatographed (20% EtOAc/hexanes on silica) to give the title compound as a white solid (1.25 g, 35%); mp 95°-102° C.
Reaction SMILES: Cl.[F:2][C:3]1[N:27]=[CH:26][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[C:14]([CH3:25])[CH:13]=3)[C:5]=2[CH:4]=1.[CH:28]1([CH2:33][C:34](Cl)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1(C(N2CCC(OC3C=CC(NC4C5C=C(F)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[CH:28]1([CH2:33][C:34]([N:22]2[CH2:23][CH2:24][CH:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:10]4[C:5]5[CH:4]=[C:3]([F:2])[N:27]=[CH:26][C:6]=5[N:7]=[CH:8][N:9]=4)=[CH:13][C:14]=3[CH3:25])[CH2:20][CH2:21]2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Reactant: O=C(Cl)CC1CCCC1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Agent: Cl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)CC2CCCC2)CC1

Procedure:
The title compound was prepared from (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine (T) and cyclopentylacetyl chloride by a procedure analogous to that described for the synthesis of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone. MS: 464.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.57 (s, 1H), δ 8.19 (s, 1H), δ 7.035 (d, J=9.97, 2H), δ 4.58-4.59 (m, 1H), δ 3.71 (m, 2H), δ 3.30-3.93 (m, 2H), δ 2.31 (d, J=7.47, 2H), δ 2.17 (s, 3H), δ 2.08-2.12 (m, 1H), δ 1.80-1.95 (m, 1H), δ 1.43-1.73 (m, 10H), δ 1.05-1.10 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:55]1[CH2:54][CH2:53][N:52]([C:43]2([CH2:42][NH:41][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:59][CH:58]=3)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]2=[O:49])[CH2:57][CH2:56]1)(=[O:18])[CH3:16]
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCN(C2(CNC(=O)c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NC(=O)NC2=O)CC1
Yield: 31 %

Procedure:
Following a procedure analogous to that used in reaction (10), the material from example 8 was reacted with acetyl chloride to provide the title compound (7 mg, 31%). MS found: (M+H)+=559.5.
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH2:31]([SH:33])[CH3:32].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1.C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:33][CH2:31][CH3:32])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CCS
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CSCC)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step L, 100 mg, 0.224 mmol) was azeotroped three times in benzene on a rotary evaporator. The residue was dissolved in toluene and transferred to a reaction vessel. The vessel was flushed with argon. Ethanethiol (33.1 μl, 0.447 mmol) was added followed by cyanomethylenetributylphosphorane (216 μl, 0.894 mmol). The vessel was sealed and the solution was heated to 100° C. for 4 h. The reaction mixture was diluted with DCM (10 ml) and Si-maleimide (Silicycle, 2.1 g; 0.66 mmol/g; 40-63 microns) was added to scavenge excess thiol. After stirring for about 1 h, the mixture was filtered and the silica gel was rinsed with DCM. The filtrate was concentrated on a rotary evaporator. The residue was dissolved in DCM and loaded directly onto a dry 12 g gold-capped Redisep® column (Teledyne Isco, Lincoln, Nebr.). The column was eluted with a gradient of 0 to 5% MeOH:DCM. The fractions containing the desired product were combined and concentrated to afford the title compound as a colorless film.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][O:4][C:5]([N:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]4[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]=4[CH:33]=3)[CH:14]=2)[N:9]=[CH:8]1)=[O:6].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:25]1[C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[C:15]4[N:7]([C:5]([O:4][CH2:3][CH:2]([CH3:34])[CH3:1])=[O:6])[CH:8]=[N:9][C:10]4=[N:11][CH:12]=3)=[CH:33][C:20]=2[CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc21
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Temperature: 80 °C
Yield: 117.4 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazo[4,5-b]pyridine-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.40 g, 0.86 mmol) in chloroform (4 mL) was added dropwise trifluoroacetic acid (5 mL) and the solution then warmed to 80° C. for 45 minutes. After cooling, the solution was concentrated and dried to give 2-methylpropyl 6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (0.37 g, 90% yield) as the trifluoroacetic acid salt. MS (EI) for C20H25N4O3: 367 (MH+).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C1C2C3C=CC(C2C=C1)C3.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1.B(F)(F)F.CCOCC>>[CH:1]12[CH2:5][CH:4]([CH2:3][CH2:2]1)[C:17]1[C:16]([O:21][C:19](=[O:20])[C:18]2=1)=[O:22]
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)O1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: O=C1OC(=O)C2=C1C1CCC2C1
Temperature: 100 °C

Procedure:
Mixed polybasic anhydride containing a plurality of 1,2 anhydrides is obtained by distilling, at 200° C., 66.10 gms. (1 mole) of cyclopentadiene directly from dicyclopentadiene into a reactor containing 98.06 gms. (1 mole) of maleic anhydride, heated to a temperature of 55° C. When the transfer is complete, the reaction mixture is heated to 100° C. for 2 hours. The reaction mixture is then stripped of any excess cyclopentadiene at 120° C. at 1 atmosphere. The resulting Diels-Adler adduct of cyclopentadiene and maleic anhydride is the anhydride of cis-5-norbornene-2,3-dicarboxylic acid. The reaction mixture is cooled to 50° C., and 4.90 gms. (0.03 moles) of boron trifluoride etherate is added slowly with stirring. The reaction mixture exotherms to 65° C. after which it is heated to 125° C., to decompose the BF3OEt and then cooled. The reaction is quenched by mixing with 3 liters of 10% sodium bicarbonate. The mixture is then neutralized with dilute 5% hydrochloric acid. The mixed polybasic anhydride of norbornene-2,3-dicarboxylic acid anhydride is obtained as a fine tan power, Mp. 200° C., and used for foam preparation without further purification.