Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]>C(Cl)Cl>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:34][C:31]=2[C:32]#[N:33])=[CH:37][C:38]=1[C:43]([F:44])([F:45])[F:46]
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(CSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 38.4 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (38 mg, 0.173 mmol) and DIPEA (0.079 mL, 0.455 mmol) in DCM (1 mL), was added 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (50 mg, 0.152 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (30 mg, 38.5% yield). LCMS: rt=3.14 min, [M+H+]=514
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cccc(CC(=O)OC)c3)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cccc(CC(=O)O)c3)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.185 mL, 0.185 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-biphenyl-3-yl)-acetic acid methyl ester (Example 124-(1); 30.8 mg, 0.062 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at room temperature for three days. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (23.8 mg, 79%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH:5]=[O:6].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].O>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:4]([CH:5]=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1]
Reactant: CC(C)(C)CCC=O
Reactant: COC(=O)CBr
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(C=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked flask fitted with a Dean-Stark apparatus under argon, a solution of dilsobutylamine (4.62 ml from Acros), 4,4-dimethyl pentanal 362 (2.5 g, 0.021 mol.) in toluene (20 ml) is heated at 130° C. for 2 h and water is extracted. The yellow solution is cooled down to room temperature and methyl bromoacetate (3.7 g, 0.024 mol.) is added in one time. The pink solution is stirred at room temperature overnight and 1 h at 90° C. Water (10 ml) is added at this temperature and after 1 h, the solution is cooled down to room temperature. The organic layer is washed with HCl 1N, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford an oil which is distilled under reduced pressure (1 mmHg) to afford 5,5-dimethyl-3-formyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mol, Teb (1 mmHg): 69-71° C.). The aldehyde esters are then used in the reductive amination step. Alternatively, alkylation with ethyl bromoacetate can be conducted in the presence of toluene-acetonitrile 1/1 (v/v) as solvent. The final aldehyde can also be distilled under reduced pressure.
Reaction SMILES: OCC1C=C(C=C(OC)C=1)C(NC1CCNCC1)=O.C[O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([CH2:31][OH:32])[CH:24]=1.[Li+].[OH-]>C1COCC1.CO>[OH:32][CH2:31][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH3:30])[CH:26]=1)[C:22]([OH:33])=[O:21]
Reactant: COC(=O)c1cc(CO)cc(OC)c1
Agent: COc1cc(CO)cc(C(=O)NC2CCNCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CO)cc(C(=O)O)c1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide [prepared by i) saponification of 3-hydroxymethyl-5-methoxy-benzoic acid methyl ester [Synthetic Communications, 31(12), 1921-1926; 2001] with LiOH in THF/MeOH (2:1) to give 3-hydroxymethyl-5-methoxy-benzoic acid in analogy to the procedure described in example 53; ii) subsequent condensation with 4-amino-piperidine-carboxylic acid tert-butyl ester to give 4-(3-hydroxymethyl-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester, using N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride and N,N-dimethyl-4-aminopyridine in MeCl2 in analogy to the procedure described in example 60d); iii) Boc cleavage with TFA in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 461.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cccc(C)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 94.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.14 g of 3-methylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.27 g of 4-(3-methylphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (29)).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:30][CH2:29]2)=[CH:25][CH:24]=1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: COCCOc1ccc(OC2CCNCC2)cc1
Product: COCCOc1ccc(OC2CCN(CC(=O)N[C@@H]3COc4nc([N+](=O)[O-])cn4C3)CC2)cc1
Yield: 56.4 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-methoxyethoxy)phenoxy)piperidine (251 mg, 1.0 mmol) as crude materials, 134 mg title compound was generated and yield was 56%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][N:6]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[S:3][C:4]([C:7]([C:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)=[O:8])=[CH:5][N:6]=2)=[CH:21][CH:20]=1
Reactant: O=C(c1cnc(Br)s1)c1c[nH]c2ncccc12
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(NCc2ccc(Cl)cc2)s1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A mixture of (2-Bromo-thiazol-5-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (99, 5 mg, 0.02 mmol), p-chlorobenzylamine (61, 10 mg, 0.08 mmol), and N,N-Diisopropylethylamine (10 μL, 0.08 mmol) in tetrahydrfuran (10 mL), in a sealed reaction vessel, was stirred room temperature overnight. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a light yellow solid (P-0077, 2 mg, 30%). MS (ESI) [M+H+]=305.90, 307.88.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[NH2:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc(N)cc(NCCNC(=O)OC(C)(C)C)n1
Temperature: 180 °C

Procedure:
6-Chloro-2-methylsulfanyl-pyrimidin-4-amine (176 mg, 1 mmol) was dissolved together with tert-butyl N-(2-aminoethyl)carbamate (200 mg, 1.25 mmol) and triethylamine (174 μl, 1.25 mmol) in THF (2 ml). The mixture was stirred at 180° C. under microwave heating for 8 hours. The mixture was diluted with ethyl acetate and the resulting solution was washed with a solution of sodium bicarbonate (5%) and brine, dried over magnesium sulfate, the volatiles were removed under reduced pressure. The residue dissolved in DCM and purified by filtration over silica to yield 105 mg (0.35 mmol, 35%) MS (ESI) m/z=300.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=O)[CH2:11][CH2:10][CH:9]([N+:14]([O-])=O)[CH2:8][C:7]=2[CH:17]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH:9]([NH2:14])[CH2:8][C:7]=2[CH:17]=1
Reactant: COc1ccc2c(c1)CC([N+](=O)[O-])CCC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(N)CCC2
Yield: 94.1 %

Procedure:
A solution of 2-methoxy-8-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.20 g) in acetic acid (2 ml) was hydrogenated at 4 atm hydrogen atmosphere over 10% palladium on carbon (0.20 g). After removing the catalyst, the pH of the solution was adjusted to 12 with sodium hydroxide solution and the solution was extracted with ethyl acetate. The extract was washed with brine, dried over potassium carbonate, and evaporated in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (153 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].O[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:36])([F:35])[F:34].CC(=O)OCC>COCCOC>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:34])([F:36])[F:35])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CS(=O)(=O)c1ccc2c(c1)C(O)N(CC(F)(F)F)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1c2cc(S(C)(=O)=O)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.56 g of a 60% suspension of NaH in mineral oil were suspended in 20 ml of DME. Afterwards, 2.8 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester were added dropwise at ambient temperature and the mixture stirred for 1 h at that temperature. A solution prepared of 3-hydroxy-5-methanesulfonyl-2-(2,2,2-trifluoro-ethyl)-2,3-dihydroisoindol-1-one using 30 ml of DME was then added and the mixture was heated up to reflux. The mixture was refluxed for 4 h and then allowed to cool to ambient temperature. 300 ml of EA were added and the mixture was washed 3 times using 100 ml of saturated aqueous NaHCO3 solution each time. The aqueous layer was then extracted twice using 100 ml of EA each time. The combined EA layers were dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using MTB yielded 1.1 g of a colorless oil (Rf(MTB)=0.40; MS (DCI): 380 (M+1)+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([O:32][CH3:33])=[O:31])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([C:26](OC)=[O:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[BH4-]>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([O:32][CH3:33])=[O:31])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH2:26][OH:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)N(C)c1ccccc1-3
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)N(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Dimethyl 13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-6,10-dicarboxylate was dissolved in anhydrous THF (0.05M) and LiBH4 (1 eq.) was added. The mixture was stirred at RT. After 1 h only marginal conversion to the product was observed. BH3.THF complex (1 eq.) was added and the mixture was stirred at RT. After 2h a further equivalent of BH3.THF complex was added and the mixture was stirred for 2 h. The mixture was quenched by addition of silica gel and all volatiles were evaporated in vacuo. The product was isolated by flash chromatography (PE:EtOAc, 8:2). After evaporation of the solvents the product was obtained as a colourless solid (80%). (ES+) m/z 419 (M+H)+.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([P:35](=[O:46])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([F:34])[F:33])=[CH:28][CH:27]=1>CN(C=O)C>[C:42]([O:41][P:35]([C:32]([F:34])([F:33])[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:2]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([P:35]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:46])([F:34])[F:33])=[CH:28][CH:27]=2)([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[CH:27][CH:28]=1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:46])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of dibenzyl malonate (0.5 g) in DMF (4 mL), was added sequentially NaH (0.12 g, 80% in mineral oil), di(tert-butyl) [[4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (1.60 g). The reaction mixture was stirred at room temperature for 1 h, then quenched with 20 mL of saturated aqueous NH4Cl solution and extracted with 50 mL EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 1:1 hexane/EtOAc to give the title compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].NC1C(Cl)=NC=NC=1Cl.CNC.[C:24](Cl)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH3:10][N:9]([CH3:11])[C:3]1[C:2]([NH:1][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:7]([Cl:8])[N:6]=[CH:5][N:4]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CN(C)c1ncnc(Cl)c1N
Agent: CNC
Agent: Nc1c(Cl)ncnc1Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(Cl)ncnc1N(C)C

Procedure:
5-Amino-4-(dimethyl)amino-6-chloropyrimidine (prepared by reacting commercially available 5-amino-4,6-dichloropyrimidine with excess dimethylamine) was coupled with oleoyl chloride according to the procedure described in Example 4 to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CN(C)S(=O)(=O)Cc1cccc(N)c1
Reaction time: 4 h
Yield: 95.8 %

Procedure:
(3-Nitrophenyl)-N,N-dimethylmethanesulfonamide (2.32 g, 9.5 mmol) was hydrogenated over Raney nickel (0.5 g) in methanol at 50° C. and 70 psi for 4 h, then catalyst was filtered off, washed with warm methanol, combined filtrates were evaporated to give 1.95 g (96%) of (3-aminophenyl)-N,N-dimethylmethanesulfonamide.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:21])([F:20])[C:10]1[C:11]([C:15]([O:17]CC)=[O:16])=[CH:12][NH:13][CH:14]=1.I[CH2:23][CH3:24]>O>[CH2:23]([N:13]1[CH:14]=[C:10]([C:9]([F:8])([F:20])[F:21])[C:11]([C:15]([OH:17])=[O:16])=[CH:12]1)[CH3:24]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a mixture of 60% sodium hydride (212 mg, 5.31 mmol) and N,N-dimethylformamide (25 mL) was added with stirring at 0° C. ethyl 4-(trifluoromethyl)-1H-pyrrole-3-carboxylate (1.00 g, 4.83 mmol), and the mixture was stirred at room temperature for 30 min. Iodoethane (581 μL, 7.24 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (4 mL) and 8N aqueous sodium hydroxide solution (2 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr and at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give the title compound (710 mg, 71%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
A mixture of 59 mg (0.1 mMol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 120 mg of 2-chloro-5-cyanopyridine and 65 mg (0.2 mMol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 5 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate-hexanes) gave the title compound (16 mg). 1H NMR: 0.88(6H,dd), 1.55-1.8(3H,m), 2.8-3.2(7h,m), 3.65(2H,m), 3.8(2H,m), 3.95(1H,m), 5.0(2H,m), 5.6(1H,d), 6.05(2H,s), 6.82(1H,d), 6.95(1H,d), 7.0(2H,d), 7.1-7.4(4H,m), 7.9(1H,d), 8.4(1H,bs). MS: 695(M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.CC1C=CC(S(O[CH2:41][C:42]2([C:45]#[N:46])[CH2:44][CH2:43]2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:41][C:42]4([C:45]#[N:46])[CH2:44][CH2:43]4)[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5(C#N)CC5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4 (5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.078 mmol) in acetonitrile (1.0 mL) was added (1-cyanocyclopropyl)methyl 4-methylbenzenesulfonate (16 mg, 0.10 mmol, prepared according to the procedure described in patent WO2005063247) followed by DIEA (30 mg, 0.23 mmol) and KI (catalytic amount). The resulting mixture was heated to 70° C. for 14 h and then cooled down to room temperature. The resulting mixture was directly purified by preparative RP-HPLC to provide 1-((4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-piperidin-1-yl)methyl)cyclopropanecarbonitrile; ESMS m/z 491.2 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:8])[CH2:6]Cl)([CH3:3])[CH3:2].[OH-:9].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH:1]([N:4]1[CH2:6][C:5](=[O:9])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:6][C:5]1=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)CCl
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CC(=O)N(C(C)C)CC1=O
Temperature: 40 °C
Reaction time: 72 h
Yield: 35.3 %

Procedure:
The compound N-isopropyl-α-chloroacetamide (2.71 g; 0.02 mole) and benzyltriethylammonium chloride (0.09 g) were dissolved in methylene chloride (50 ml) in a 100 ml flask. A 50% by weight sodium hydroxide solution (16 g) was added to the mixture, and the mixture was stirred vigorously at 40° C. for three days. Thereafter, the organic phase was separated, dried and evaporated. The residue of the evaporation (found to be four parts product per part starting material) was recrystallized from ethyl alcohol to yield 0.7 g (36%) of 1,4-diisopropyl-2,5-diketopiperazine. All spectral data were consistent with this structure.