Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH:21]=[CH2:20]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a mechanically stirred solution of 4-fluoro-3-nitro-benzoic acid (113.0 g, 0.61 mol, 1.0 equiv) in DMF (770 ml) was added portionwise potassium carbonate (168.7 g, 1.22 mol, 2.0 equiv). Allyl bromide (110.8 g, 0.92 mol, 1.5 equiv) was added to the reaction mixture and stirring continued at rt overnight. The reaction mixture was filtered, the filtrate poured into water (4 L), kept for 2 h and then extracted with ethyl acetate (3×1 L). The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The residue was purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (100:0→98:2) to obtain 114.1 g (83%) of the title compound. 1H NMR (400 MHz, DMSO): δ 4.86 (d, J=5.4 Hz, 2H), 5.30 (d, J=10.6 Hz, 1H), 5.43 (d, J=17.2, 1H), 6.01-6.10 (m, 1H), 7.73-7.78 (m, 1H), 8.34-8.37 (m, 1H), 8.60 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[N:10]3[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=[C:9]3[C:6]2=[N:7][CH:8]=1)[CH3:2].Cl.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[NH:10][C:13](=[O:20])[C:14]([CH:17]([CH3:18])[CH3:19])([CH3:16])[N:15]=2)=[C:5]([CH:4]=1)[C:11]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:12])[CH3:2]
Reactant: CCc1cnc2c(c1)C(=O)N1C(=O)C(C)(C(C)C)N=C21
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 7-ethyl-2-isopropyl-2-methyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-3(2H),5-dione (7.25 g, 26.75 mmol) in anhydrous N,N-dimethylformamide is treated successively with methyl 6-aminocaproate hydrochloride (5.10 g, 28.1 mmol) and triethylamine (3.00 g, 29.6 mmol). The resulting mixture is stirred at room temperature under nitrogen for 20.5 hours. After this period, the reaction mixture is partitioned between water and ethyl acetate. The layers are separated, and the organic layer is washed with water, dried over magnesium sulfate and vacuum filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain a white solid. The solid is triturated with 1:1 ether/petroleum ether to give the title product as a white solid (7.40 g, 69%, mp 101°-103° C.).
Reaction SMILES: Cl.[C:2](=[NH:9])([NH2:8])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[O-]CC.[Na+].C(O[CH:17]=[CH:18][C:19](=O)[C:20]([F:23])([F:22])[F:21])C>C(O)C>[CH2:3]([C:2]1[N:8]=[C:19]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:17][N:9]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCC(=N)N
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCCCc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-hexenimidamide hydrochloride (P4, 200 mg) in ethanol (1.8 mL), sodium ethoxide (92 mg) was added and the mixture stirred at r.t. for 5 min. 4-(Ethyloxy)-1,1,1-trifluoro-3-buten-2-one (0.13 mL) was then added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated, the residue was dissolved in dichloromethane and the organic layer was washed with H2O and dried over Na2SO4. This solution was filtered and the filtrate was concentrated in vacuo. The crude was purified by column chromatography (eluting with dichloromethane/methanol 95/5) to give 143 mg of the title compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:40])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([Sn](CCCC)(CCCC)CCCC)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH2:52])=[N:44][CH:43]=1>>[C:1]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[N:13]([CH3:40])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([C:42]2[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:45]([NH2:52])=[N:44][CH:43]=2)[N:15]=3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)C)CC3)n(C)c2n1
Reactant: Nc1ncc(Br)c2ccccc12
Product: Cn1c(CN2CCC(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)c4ccccc34)nc21

Procedure:
4-(8-((4-tert-butylpiperidin-1-yl)methyl)-9-methyl-2-(tributylstannyl)-9H-purin-6-yl)morpholine (0.1 g) was reacted with 4-bromoisoquinolin-1-amine via General Procedure D to afford 114 (10 mg) following reverse phase purification. MS (Q1) 515.3 (M)+. 1H NMR (500 MHz, CDCl3) δ 9.02 (d, 1H), 7.94-7.45 (m, 6H), 4.35 (s, 4H), 4.02-3.61 (m, 9H), 2.97 (s, 2H), 2.13 (s, 2H), 1.92-1.52 (m, 5H), 1.52-0.68 (m, 26H)
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10]>CN1CCCC1=O>[C:1]([O:4][CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])(=[S:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: FC(F)(F)CCBr
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=S)OCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a suspension of 7.35 g of potassium thioacetate in 30 ml of N-methyl-2-pyrrolidone was added dropwise 11.39 g of 3-bromo-1,1,1-trifluoropropane over 15 minutes at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was heated to 80° C., followed by distillation under reduced pressure to obtain 9.99 g of 3,3,3-trifluoropropyl thioacetate represented by the formula:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@H:8]2[CH2:9][C@H:5]([CH2:6][CH2:7]2)[C@H:4]1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:28].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C@H:3]2[C@H:8]3[CH2:9][C@H:5]([CH2:6][CH2:7]3)[C@H:4]2[C:10]([O:12][CH3:13])=[O:11])=[CH:22][C:21]=1[CH3:28]
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
Methyl (1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (prepared as described in Example 6c, 0.32 g, 1.56 mmol) was dissolved in methanol (8 mL). Sodium acetate (0.26 g, 3.12 mmol) was added followed by 4 Å powdered molecular sieves (0.32 g) and 4-fluoro-3-methyl benzaldehyde (0.19 mL, 1.56 mmol). Sodium cyanoborohydride (0.24 g, 3.12 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1S,2R,3S,4R)-3-(4-fluoro-3-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylate (0.35 g, 1.20 mmol, 77%), as a clear oil. LC-MS (ESI) calcd for C17H22FNO2 291.36. found 292.5 [M+H+].
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH3:9])([OH:3])=[O:2].[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:4]1[S:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[CH3:9])([OH:3])=[O:2]
Reactant: Cc1ccsc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])sc1C(=O)O
Yield: 53 %

Procedure:
To a solution of 2-carboxy-3-methylthiophene (10 g, 70.3 mmol) in 80 mL of trifluoroacetic acid at 0° C. was added HNO3 (1.2 mL,1.0 eq.) dropwise. The reaction mixture was warmed to ambient temperature and after 4 hours another 1.0 eq. of HNO3 was added. The reaction mixture was made basic with aqueous sodium bicarbonate and washed with ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 5.75 g (53%) of 2-carboxy-3-methyl-5-nitrothiophene and 2-carboxy-3-methyl-4-nitrothiophene, as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[S:16](=[O:18])(=[O:17])[N:15]([CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14](=[O:28])[CH2:13]2)=[C:7]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1.CCOC(C)=O>[CH2:30]([O:29][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[C:8]=1[N:12]1[CH2:13][C:14](=[O:28])[N:15]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[S:16]1(=[O:17])=[O:18])[CH2:4][C:3]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:2]=1[NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[4-(2-amino-4-methylbenzyl)-2-benzyloxy-6-fluorophenyl]-2-benzyloxymethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg, 0.42 mmol) in pyridine (5 mL) is added methanesulfonyl chloride (0.064 mL, 0.84 mmol) and the solution is stirred at RT for 2 h. The mixture is then diluted in EtOAc, and it is washed with 1N HCl, brine and water. The organic layer is dried with MgSO4, and concentrated. The residue is purified to give the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH2:2][CH3:3].[CH3:13][O:14][C:15]1[CH:26]=[C:25]2[C:18]([NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.[BH4-].[Na+]>CCO>[CH3:13][O:14][C:15]1[CH:26]=[C:25]2[C:18](=[CH:17][CH:16]=1)[NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH:24][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1
Reactant: CCCOc1cccc(C=O)c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1cccc(CNCCc2c[nH]c3ccc(OC)cc23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 3-propoxybenzaldehyde (14.05 g, 0.0856 mole) and 5-methoxytryptamine (13.64 g, 0.0717 mole) in 390 mL absolute EtOH. Add molecular sieves (19.2 g) and heat the suspension to reflux. After 4 hours, cool to room temperature and add NaBH4 (37.32 g, 0.2146 mole) in 3 portions. Stir the mixture for 1 hour at room temperature, filter, evaporate the filtrate to a mass of about 100 g, add water and dichloromethane. After separation, wash the aqueous phase with dichloromethane, combine the organic layers, dry over MgSO4, filter, evaporate the solvent in vacuo to afford the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C@@H:12]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15](=[O:17])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[C@@H:12]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14][C@@H:15]([OH:17])[CH:16]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 85.4 %

Procedure:
The title compound was prepared from (S)-tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 280, 8.55 g, 17.11 mmol) according to the procedure described for Intermediate 8 to afford the desired product (7.33 g, 85%) as a light yellow oil.
Reaction SMILES: [CH:1]1([C@@H:4]2[O:13][CH2:12][C:7]3=[N:8][O:9][C@@H:10]([CH3:11])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C1([C@@H]2OC[C@]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:13][CH2:12][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[NH:8][O:9][C@@H:10]([CH3:11])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Product: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
(3S,3aR,5R)-5-Cyclopropyl-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C27) was converted to the product according to the method described for synthesis of rel-(3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) in Example 2. The product was obtained as a gum. Yield: 60 mg, 0.20 mmol, 40%. 1H NMR (400 MHz, CDCl3) δ 7.99 (ddd, J=9.2, 9.0, 6.8 Hz, 1H), 6.90 (dddd, J=8.9, 7.9, 2.6, 1.0 Hz, 1H), 6.79 (ddd, J=11.9, 8.7, 2.5 Hz, 1H), 6.31 (br s, 1H), 4.03-4.10 (m, 1H), 3.89 (dd, half of ABX pattern, J=12.8, 2.0 Hz, 1H), 3.80 (br dd, half of ABX pattern, J=12.8, 1.5 Hz, 1H), 2.79-2.91 (m, 2H), 2.16 (ddd, J=14.3, 7.5, 2.5 Hz, 1H), 1.64 (dddd, J=14.2, 10.7, 10.7, 1.7 Hz, 1H), 0.90-0.99 (m, 1H), 0.79 (d, J=6.5 Hz, 3H), 0.52-0.64 (m, 2H), 0.39-0.45 (m, 1H), 0.24-0.31 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1)=O.N1CCCCC1.[CH2:17]([N:21]1[C:26]([NH:27][N:28]=[CH:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=3)[NH:32][CH:31]=2)=[CH:25][C:24](=[O:40])[N:23]([CH3:41])[C:22]1=[O:42])[CH:18]([CH3:20])[CH3:19]>CN(C)C=O>[Cl:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH2:29][N:28]1[C:1]([C:3]2[N:7]([CH3:8])[CH:6]=[C:5]([C:9]#[N:10])[CH:4]=2)=[C:25]2[C:26]([N:21]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:22](=[O:42])[N:23]([CH3:41])[C:24]2=[O:40])=[N:27]1
Reactant: Cn1cc(C#N)cc1C=O
Reactant: CC(C)Cn1c(NN=Cc2c[nH]c3ccc(Cl)cc23)cc(=O)n(C)c1=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C#N)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Temperature: 50 °C
Yield: 59 %

Procedure:
5-formyl-1-methyl-1H-pyrrole-3-carbonitrile (0.032 g) and piperidine (0.05 ml) was added to a solution of 5-chloro-1H-indole-3-carbaldehyde (3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (0.075 g) in dimethylformamide (1.5 ml). The solution was heated at 50° C. for 5 hours. Reaction cooled to room temperature and purified on preparative HPLC to give the title compound (0.058 g). Mass: 490.16 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:17])[CH2:10][CH2:11][CH:12]2[O:14]C2(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.I([O-])(=O)(=O)=O.[K+]>O>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:17])[CH2:10][CH2:11][CH:12]=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](CCC1CCCCC1)CCC1OC1(C)C
Agent: [K+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](CCC=O)CCC1CCCCC1
Reaction time: 46 h
Yield: 81.1 %

Procedure:
A flask was charged with 10.65 g (44.7 mmol) of 3-((R)-5-cyclohexyl-3-methyl-pentyl)-2,2-dimethyl-oxirane, 70 mL of acetone, 12.3 g (53.6 mmol) of potassium periodate, 70 mL of water, and 0.765 g (4 mmol) of tosic acid-monohydrate. The mixture was stirred for 46 hours. The acetone was removed under reduced pressure, and the mixture was diluted with water. The aqueous layer was extracted with hexanes and dried with sodium sulfate. The drying agent was filtered off and solvent was removed under reduced pressure to get 7.12 g (81% yield) of a clear oil: 1H NMR (400 MHz, CDCl3) ppm 0.87 (m, 5H) 1.13 (m, 3H) 1.25 (m, 5H) 1.66 (m, 8H) 2.40 (m, 2H) 9.75 (s, 1H). MS (APCI) m+1/z is inconclusive.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([O:32][CH:33]([CH3:35])[CH3:34])[CH:26]=1.C(OCC)(=O)C>C1COCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:7](=[O:8])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:27]([O:32][CH:33]([CH3:35])[CH3:34])[CH:26]=1
Reactant: COc1cnccc1-c1ccc(N)c(OC(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cnccc1-c1ccc(NC(=O)OCc2ccccc2)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 ml of a saturated aqueous sodium bicarbonate solution and then 3.81 ml of benzyl chloroformate are added to a solution of 4.6 g of 4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)aniline in 115 ml of THF. The reaction medium is stirred overnight at ambient temperature and then 3.81 ml of benzyl chloroformate are added and the reaction medium is stirred at ambient temperature for 2 hours. 2.54 ml of benzyl chloroformate are added and the reaction medium is stirred for a further 2 hours at ambient temperature. The reaction medium is poured into 100 ml of ethyl acetate and 50 ml of water. The two phases are separated and the aqueous phase is extracted with twice 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified on 100 g of silica, elution being carried out with dichloromethane/acetone (100/0 to 95/5), so as to give 3.12 g of benzyl [4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([CH2:16][CH:17]([N:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][CH2:21]2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][CH2:21]1)[CH2:16][C:13]1([F:12])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC(CC1(F)CC1)N1C=CC(C(F)(F)F)=NC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(F)CC1)N1C=CC(C(F)(F)F)=NC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=436.1, tR (minutes, Method G)=2.61
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[CH3:8].[C:9]([C:13]1[N:14]([CH3:25])[S:15](=[O:24])(=[O:23])[C:16]2[CH:22]=[CH:21][S:20][C:17]=2[C:18]=1[OH:19])(OC)=[O:10]>>[CH3:7][C:4]1[C:3]([CH3:8])=[C:2]([NH:1][C:9]([C:13]2[N:14]([CH3:25])[S:15](=[O:24])(=[O:23])[C:16]3[CH:22]=[CH:21][S:20][C:17]=3[C:18]=2[OH:19])=[O:10])[O:6][N:5]=1
Reactant: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Reactant: Cc1noc(N)c1C
Product: Cc1noc(NC(=O)C2=C(O)c3sccc3S(=O)(=O)N2C)c1C

Procedure:
By reacting 5-amino-3,4-dimethyl-isoxazole with 3-carbomethoxy-4-hydroxy-2-methyl-thieno[2,3-e]-1,2-thiazine 1,1-dioxide for 14 hours in a manner analogous to that described in Example 1, there is obtained N-(3,4-dimethyl-5-isoxazolyl)-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of decomposition point 206°-208° C. (recrystallization from benzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([OH:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([OH:46])[OH:45])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: NCCCP(O)O
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added (25) (100 mmol), 3-aminopropylphosphonous acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (39) as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH:37]=O)[CH3:32].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][CH3:44])=[C:34]([O:33][CH2:31][CH3:32])[CH:35]=2)[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1OCC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 3,4-diethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) and the solution was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.125 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compound No. 2065) (21.2 mg, 84%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 505.2 (M++H, C26H34F2N4O4).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][CH:17]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.Cl[C:31]1[CH:50]=[CH:49]C=CC=1C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH:8]([NH:12][CH:50]([CH3:49])[CH3:31])([CH3:9])[CH3:7].[NH:12]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][CH:4]1[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: CC(C)NC(C)C

Procedure:
Fmoc Cha-OH (1 mmol each time) was double coupled to the chlorotrityl chloride resin in the standard way using, dichloromethane (5 ml each time) with diisopropylamine (2 eq, 348 μl each time) to give Fmoc-Cha-resin.