Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[CH3:17]C(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[CH2:52]([O:54][C:55](=[O:59])[CH2:56][CH2:57][Zn+])C.C1COCC1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][C:12]([CH3:13])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([CH2:57][CH2:56][C:55]([O:54][CH3:52])=[O:59])=[CH:3][CH:4]=2)[N:8]([CH3:16])[C:9]1=[O:15]
Reactant: CCOC(=O)CC[Zn+]
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C

Procedure:
To a stirred solution of 1-4 (0.10 g, 0.39 mmol), Pd(OAc)2 (0.004 g, 0.02 mmol), xphos (0.02 g, 0.039 mmol) in dioxane (3 mL) was added 3-ethoxy-3-oxopropylzinc bromide 0.5M solution in THF (3.15 mL, 1.57 mmol) and the resulting mixture was microwave irradiated for 30 minutes at 100° C. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic phase was concentrated and flash column separation using a 0-30% ethyl acetate/hexane gradient gave 37-1. (0.10 g, 86%). LRMS (ES) (M+H)+: observed=320.1, calculated=320.4.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:5][CH:4]=1)[CH3:2].CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCc1ccc(CCc2ccccc2O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1ccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Yield: 99.3 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.00 g of 2-[2-(4-ethylphenyl)ethyl]phenol (prepared as described in Preparation 26), 0.496 g of potassium t-butoxide and 1.70 g of 1-t-butoxycarbonyl-2-[2-(p-toluenesulfonyloxy)ethyl]piperidine were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.92 g (yield 99%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][CH:2]([N:4]1[C:8]2[CH:9]3[CH2:20][CH:11]([C:12]4[CH:17]=[C:16]([F:18])[C:15](I)=[CH:14][C:13]=4[C:7]=2[N:6]=[C:5]1[C:21]([NH2:23])=[O:22])[CH2:10]3)[F:3].[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>N1CCCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][CH:2]([F:3])[N:4]1[C:8]2[CH:9]3[CH2:20][CH:11]([C:12]4[CH:17]=[C:16]([F:18])[C:15]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])=[CH:14][C:13]=4[C:7]=2[N:6]=[C:5]1[C:21]([NH2:23])=[O:22])[CH2:10]3
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2c(n1C(F)F)C1CC(C1)c1cc(F)c(I)cc1-2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)c1c-2nc(C(N)=O)n1C(F)F
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
To a solution of -(difluoromethyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (12 mg at 80% purity LCMS-UV215) in piperidine (0.5 mL) was introduced 2-methyl-3-butyn-2-ol (12 mg, 0.14 mmol) and copper(I) iodide (0.3 mg, 0.001 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (0.6 mg, 0.001 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (2×7 mL), water (2×7 mL) and brine (7 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Partial purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile/water (3:1, 0.4 mL). Filtration furnished the title compound (4.5 mg, 0.011 mmol, 6% over 3 steps) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.67 (s, 6H), 1.73 (d, J=11.35 Hz, 2H), 2.93-3.04 (m, 2H), 3.60 (td, J=7.96, 3.31 Hz, 1H), 3.84-3.92 (m, 1H), 5.56 (br. s., 1H), 6.87 (d, J=10.09 Hz, 1H), 7.42 (br. s., 1H), 8.40 (d, J=7.57 Hz, 1H), 8.75 (t, J=58.40 Hz, 1H); M+H=390.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][C:11]([CH3:16])([CH3:15])[NH:10]2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=1.C(N(CC)CC)C.Cl.C(OCC)(=O)C>O1CCCC1>[ClH:2].[ClH:17].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:18]3[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[N:19]=3)[CH2:12][C:11]([CH3:16])([CH3:15])[NH:10]2)=[CH:7][CH:8]=1
Reactant: CC1(C)CNCC(c2ccc(Cl)cc2)N1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CC(c3ccc(Cl)cc3)NC(C)(C)C2)nc(-c2ccncc2)cc1=O
Yield: 187.2 %

Procedure:
A solution of 2-(4-chlorophenyl)-6,6-dimethyl-piperazine hydrochloride (155 mg, 0.52 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (111 mg, 0.50 mmol) and triethylamine (0.42 mL, 2.50 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 6 h. The whole was evaporated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with water, dried and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and treated with 4M hydrogen chloride in ethyl acetate (0.50 mL, 2.0 mmol) for 20 min. After removing the solvent, filtrating and washing the precipitate with ethanol gave 2-(2-(4-chlorophenyl)-6,6-dimethyl-piperazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one dihydrochloride (235 mg, 97%).
Reaction SMILES: [CH3:1][CH:2](C)[C:3](NC1C=CC(C2CCNCC2)=CC=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(Cl)(=O)CC>>[NH:29]1[CH2:28][CH2:27][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:3](=[O:4])[CH2:2][CH3:1])[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: CCC(=O)Cl
Product: CCC(=O)Nc1cccc(C2CCNCC2)c1

Procedure:
Prepared by the procedure for 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide using tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate and propanoyl chloride: Anal. Calcd for C14H20N2O: C, 72.2; H, 8.63; N, 12.1. found: C, 72.4; H, 8.68; N, 12.1; ESMS m/e: 233.1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=3[F:37])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=[O:3])[CH3:2].CC[N:40]([CH:44](C)C)[CH:41]([CH3:43])[CH3:42].ClC(Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:44]([NH:40][CH:41]4[CH2:42][CH2:43]4)=[O:50])=[CH:32][C:31]=3[F:37])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)COC(C)=O
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)COC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 114.9 %

Procedure:
To a solution of 207 (130 mg, 0.246 mmol) in THF (20 mL) at 0° C. was added DIPEA (0.172 mL, 0.986 mmol) and triphosgene (43.9 mg, 0.148 mmol). The reaction mixture was stirred for 1 hr at 0° C. before cyclopylamine (70.3 mg, 1.232 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hr before concentration. The residue was purified by Biotage (MeO/DCM, 0-20%, SNAP 25 g cartridge) to give the title compound 208 (104 mg, 0.170 mmol, 69% yield) as a white solid. MS: 611 (MH)+.
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[N:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][NH:26]3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:30][S:31]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:6]([OH:40])=[O:5])=[O:29])=[CH:12][CH:13]=3)[N:28]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1

Procedure:
A solution of 32-6 (221 mg, 0.39 mmol), TFA (5 mL) and CH2Cl2 (50 mL) was stirred under ambient conditions for 18 h. The reaction was concentrated and the solid residue purified by flash chromatography (silica, 19:1 EtOH/NH4OH) to give 32-7 as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:13]=1[S:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 4-amino-2,6-dichlorophenol (Aldrich, 5.9 g, 33 mmol) in 30 mL of THF was added 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (4.19 g, 15 mmol). The mixture was stirred overnight. The reaction mixture was filtered and washed with EtOAc. The filtrate was washed with 2N HCl, twice with a brine solution, dried over Na2SO4 and concentrated. The residue was purified by chromatography (20%-25% EtOAc/hexanes) to give 5.7 g (90%) of product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].[CH2:18]([N:25]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:18]([N:25]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
Diisopropylethylamine and tert-butyldimethyl-chlorosilane were added in that order to a chloroform solution of (1-benzylpyrrolidin-3-yl)methanol and stirred at room temperature for 5Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl]pyrrolidine. EP: 306.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[K+].COS(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester, from Example (55d) (389 mg) was dissolved in THF (3 ml) and cooled to −78° C. prior to the slow addition of a solution of 0.5M KHMDS in THF (2.65 ml). After 20 min, Me2SO4 (0.15 ml) was added. The reaction was warmed to rt and stirred for 2 h before the solution was quenched with sat. NH4Cl. This was extracted twice with EtOAc. The combined organic layer was dried, filtered, and concentrated. Flash chromatography of the resulting residue gave ±(1S*,2R*,4R*)-[4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester (207 mg): 1H NMR (CDCl3, δppm, 300 mHz) 1.39 (s, 9H), 1.55-1.93 (m, 4H), 2.00 (m, 1H), 2.52 (s, 3H), 2.65 (m, 1H), 2.80 (s, 3H), 3.00 (m, 2H), 3.81 (m, 3H), 7.34 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [NH:1]1[C:5]([CH:6]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH3:7])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH2:30]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(Cl)Cl.C1C=CC=CC=1>[NH:4]1[C:5]([CH:6]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:45][CH:44]=2)[CH3:7])=[N:1][N:2]=[N:3]1
Reactant: CC(Oc1cccc(Oc2ccccc2N)c1)c1nnn[nH]1
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Oc2cccc(OC(C)c3nnn[nH]3)c2)cc1
Temperature: 0 °C
Yield: 62.1 %

Procedure:
In 30 ml of methylene chloride were dissolved 2.1 g of 2-[3-[1-(1H-tetrazol-5-yl)ethoxy]phenoxy]aniline and 2.2 g of triethylamine, followed by dropwise addition of a solution of 1.7 g of 4-hexyloxybenzoyl chloride in benzene with ice-cooling and stirring. The mixture was stirred at room temperature overnight and refluxed for 1 hour. To the reaction mixture was added ice-water and after the mixture was acidified with diluted hydrochloric acid, the methylene chloride layer was separated. The methylene chloride solution was dried over magnesium sulfate and concentrated and the oily residue was subjected to silica gel column chromatography using chloroform-methanol (100:1) as the eluent to give 2.2 g of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[O:9]=[C:10]([CH3:14])[C:11](Cl)=[O:12].Cl>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:12])[C:10](=[O:9])[CH3:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C(=O)Nc1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
26.3 g of 4-chlorophenylamine in 150 ml of dichloromethane and 35 ml of triethylamine are added, at −60° C., to 22 g of 2-oxopropionyl chloride (prepared according to Synthesis, 1975, 163-164 from 2-oxopropionic acid and 1,1-dichlorodimethyl ether) in 350 ml of dichloromethane. The reaction mixture is stirred at −60° C. for 2 hours and then 200 ml of a 0.15N aqueous hydrochloric acid solution and 500 ml of dichloromethane are added at −30° C. The organic phase is extracted, washed with a 0.25N aqueous hydrochloric acid solution and dried over sodium sulphate. The solvents are evaporated under reduced pressure and the residue obtained is crystallized from dichloromethane;
Reaction SMILES: Br[C:2]1[C:3]([NH:13][CH3:14])=[N:4][CH:5]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:28]>[Cu+2].C(CC(=O)C)(=O)C.O.CN1C(=O)CCC1>[CH3:14][NH:13][C:3]1[C:2]([NH2:28])=[CH:7][C:6]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1
Reactant: CNc1ncc(SC(F)(F)F)cc1Br
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)CC(C)=O
Product: CNc1ncc(SC(F)(F)F)cc1N
Temperature: 110 °C
Reaction time: 8.5 h

Procedure:
To a pressure-resistant reaction container, (3-bromo-5-trifluoromethylsulfanylpyridine-2-yl)-methylamine (1.96 g), acetylacetone copper (II) (89 mg), acetylacetone (0.27 g), cesium carbonate (2.34 g), and NMP (7 ml), 28% of aqueous ammonia (5 ml) was added, and stirred at 110° C. for 8.5 hours. After the mixture was cooled to room temperature, into the reaction mixture, water was poured. The insoluble material was filtered through Celite®, and then the filtered material was washed with ethyl acetate, and filtrate was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.18 g of N2-methyl-5-trifluoromethylsulfanylpyridine-2,3-diamine (Compound (1F)-3).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[NH2:8].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:8][C:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[N:3]([CH3:12])[C:2]=1[NH2:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: CC(=O)Nc1c(N)n(C)c(=O)n(C)c1=O

Procedure:
A mixture of acetic anhydride (50 ml) and 4,5-diamino-1,3-dimethylpyrimidine-2,6-dione (5.4 g) was heated at reflux for 30 minutes. The mixture was then cooled, and the crystalline matter which separated was filtered off to give 5-acetylamino-4-amino-1,3-dimethylpyrimidine-2,6-dione as white needles. A suspension of oil-free sodium hydride (1.3 g) in dry dimethylformamide (5.0 ml) was stirred under nitrogen at 0° C. while the acetylamino compound was added. The mixture was then stirred for 30 minutes. Diethylaminoethyl chloride hydrochloride (4.64 g) was added, then the mixture was warmed to room temperature and stirred for 3 hours. Water was added, and the mixture was extracted with chloroform. The organic extracts were washed with water, dried and filtered, and the filtrate was evaporated to dryness. The solid residue was treated with 2 N aqueous sodium hydroxide (50 ml) at 100° C. for 30 minutes, then the mixture was extracted with chloroform, dried, filtered and evaporated to dryness. The oil product was dissolved in ethanol, treated with ethanolic hydrogen chloride and evaporated to dryness. The residue was recrystallised from isopropyl alcohol to give 8-methyl-7-(2-diethylaminoethyl)theophylline hydrochloride (3.1 g), mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[K+].[Br-].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>C(#N)C>[Br-:10].[CH2:11]([C:32]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH3:23])[C:33]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCCCCCCCCBr
Reactant: BrCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-bromononane (1.72 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a yellow/white precipitate (2.73, 56% yield). 1H NMR (500 MHz, DMSO-d6) 9.63 (1H, s, NCHN), 7.99 (4H, m, Ar), 7.58 (3H, m, Ar), 5.66 (2H, s, NCH2), 4.22 (2H, t, NCH2), 1.82 (2H, tt, CH2), 1.25 (12H, m, CH2), 0.93 (3H, t, CH3). MS: m/z=402.8 (theor for C23H29Cl2N2Br1=484.31).
Reaction SMILES: [NH2:1][C@@H:2]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH:6]1[C:14]([NH:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])=[O:15])=[O:4].[C:31]([O:35][C:36]([N:38]([CH3:44])[C@@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:14]([CH:6]1[N:5]([C:3](=[O:4])[C@@H:2]([NH:1][C:40](=[O:41])[C@@H:39]([N:38]([CH3:44])[C:36](=[O:37])[O:35][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:43])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:15]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101 %

Procedure:
To a solution of 1-((S)-2-amino-2-(tetrahydropyran-4-yl)acetyl)-N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (37 mg, 88.9 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (27.1 mg, 133 μmol, Eq: 1.5) and diisopropyl-ethylamine (62 μL, 355 μmol, Eq: 4) in DMF was added HATU (60.8 mg, 160 μmol, Eq: 1.8) and the resulting solution was stirred at rt. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was then washed with 0.1 M aqueous NaOH and brine and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 100% EtOAc in hexanes) to give tert-butyl (2S)-1-((1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (54 mg), m/z=602 (M+H).
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])[C:3]([O:5]CC1C=CC=CC=1)=[O:4].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)=[O:35]>CN(C)C1C=CN=CC=1>[CH2:25]([S:32]([CH2:1][CH:2]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:3]([OH:5])=[O:4])=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)=O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: SCc1ccccc1
Agent: CN(C)c1ccncc1
Product: O=C(O)CCC(CS(=O)Cc1ccccc1)C(=O)O
Yield: 90 %

Procedure:
To a solution of dibenzyl 2-methylenepentanedioate (12.16 g, 37.5 mmol) in acetone (100 ml), was added benzylmercaptan (9.31 g, 75.0 mmol) and 4-dimethylaminopyridine (0.46 g, 3.75 mmol) with stirring. The reaction mixture was refluxed for 16 hours. The cooled solution was concentrated under reduced pressure and purified by column chromatography to yield 15.2 g (90%) of clear oil. 1H NMR (CDCl3): δ 2.0 (m, 2H), 2.3 (m, 2H), 2.5 (m, 1H), 2.6 (m, 2H), 3.6 (s, 2H), 4.9 (s, 2H), 5.0 (m, 2H), 7.2-7.5 (m, 15H).