Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH3:20])[CH:3]=[CH:4][C:5]=1[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])#[N:8]
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1C#N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
To 15C (450 mg, 2 mmol) in pyridine (10 mL) at 0° C. was added methyl chloroformate (0.8 mL, 10 mmol). The reaction was stirred at 0° C. for 20 min, then warmed to rt for 2 h. The reaction was concentrated, then diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-60% ethyl acetate/hexanes) to provide 15D (490 mg, 88%). LC-MS: 283.35 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1Br)(=[O:3])[CH3:2].[Cu](C#N)[C:11]#[N:12]>CN1C(=O)CCC1.O>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:11]#[N:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sccc1Br
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1sccc1C#N
Yield: 99.8 %

Procedure:
Heat a stirred solution of 2-acetyl-3-bromothiophene (1.49 g, 7.29 mmol) (Chem. Pharm. Bull. 2000, 48, 1558-1566) in dry NMP (72 mL) for 10 h at 150° C. in the presence of copper cyanide (3.26 g, 36.5 mmol). Dilute the mixture with water, extract three times with diethyl ether, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give the desired intermediate as a dark oil (1.1 g, 99%).
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].OO.[CH3:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH:18]=[C:19]([C:24]#[N:25])[C:20]=3[NH:21]2)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C>[CH3:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[C:17]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:18]=[C:19]([C:24]([NH2:25])=[O:2])[C:20]=3[NH:21]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cc(C#N)c3[nH]c4cc(OC)ccc4c3c2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OC)ccc4c3c2)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 56.4 %

Procedure:
Aqueous sodium carbonate (3 M, 700 μL, 2.10 mmol) and aqueous hydrogen peroxide (30%, 700 μL, 6.79 mmol) were added to a suspension of 7-methoxy-3-(4-methoxyphenyl)-9H-carbazole-1-carbonitrile (69 mg, 0.21 mmol) in ethanol (10 mL). The mixture was heated overnight at 60° C. Sodium hydroxide (84 mg, 2.10 mmol) and additional aqueous hydrogen peroxide (30%, 700 μL, 6.79 mmol) were added and heating was continued for a further 17 hr. The ethanol was removed on the rotary evaporator and the white precipitate was collected by filtration, washed with water, and dried under vacuum. Silica gel radial chromatography using step gradient elution with hexane containing 25 to 100% ethyl acetate gave 7-methoxy-3-(4-methoxyphenyl)-9H-carbazole-1-carboxamide (41 mg, 54% yield) as a white solid. MS (ESI) m/z 347.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.21 (1H, s), 8.45 (1H, d, J=1.22 Hz), 8.29 (1H, br. s.), 8.13 (1H, d, J=1.53 Hz), 8.09 (1H, d, J=8.55 Hz), 7.80 (2H, d, J=8.55 Hz), 7.47 (1H, br. s.), 7.29 (1H, d, J=2.44 Hz), 7.07 (2H, d, J=8.55 Hz), 6.81 (1H, dd, J=8.55, 2.14 Hz), 3.84 (3H, s), 3.83 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[O:10]=[C:11]1[NH:20][CH:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[S:29]([CH3:32])(=[O:31])=[O:30])[C:18]2[C:17](=[O:33])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>CN(C)C=O.O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH:19]2[C:18]3[C:17](=[O:33])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=3)[C:11](=[O:10])[N:20]2[CH2:2][C:3]([OH:5])=[O:4])=[C:22]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:23]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl bromoacetate (200 L, 1.35 mmol) is added to a mixture of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18, 440 mg, 0.90 mmol) and cesium carbonate (440 mg, 1.35 mmol) in N,N-dimethylformamide (5 mL), and the mixture is stirred at room temperature for 3 h. Another portion of tert-butyl bromoacetate (200 μL, 1.35 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the mixture is extracted with ethyl acetate. The phases are separated and the organic layer is concentrated under reduced pressure. The residue is dissolved in acetonitrile (3 mL), and the mixture is treated with trifluoroacetic acid (10 mL, 123 mmol) and stirred at room temperature for 6 h. All volatiles are removed under reduced pressure, and the residue is directly used in the next step without further purification. Yield: 460 mg.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[CH3:44][CH2:45][CH:46](O)[CH2:47][CH3:48].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][CH:46]([CH2:47][CH3:48])[CH2:45][CH3:44])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCC(O)CC
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OC(CC)CC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (300 mg) and 3-pentanol (63 mg) are dissolved in tetrahydrofuran (4 ml), and thereto are added dropwise triphenylphosphine (189 mg) and a 40% diethyl azodicarboxylate in toluene (130 μl) under ice-cooling, and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethyl-propoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (195 mg). MS (m/z): 696 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:6]2[NH:7][C:8]([CH3:13])([CH3:12])[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.Cl.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Mg+2].[C:31]1(=O)[CH2:36]CCC[CH2:32]1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CO>[Br:1][C:2]1[C:6]2[NH:7][C:8]3([CH2:12][CH2:36][CH2:31][CH2:32][CH2:13]3)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1
Reactant: O=C1CCCCC1
Reactant: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)c(Br)c2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NC2(CCCCC2)Nc2c1sc(-c1cn[nH]c1)c2Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A mixture of 7-bromo-2,2-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (50 mg, 0.153 mmol), 1 M HCl (0.5 mL, 0.50 mmol) and MeOH (2.5 mL) was stirred at 50° C. After 1 h, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with MgSO4 (18.4 mg, 0.153 mmol), cyclohexanone (1 mL, 9.65 mmol), PTSA (2.9 mg, 0.015 mmol) and DMF (1 mL). The mixture was stirred at 80° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to EtOAc). Then, the obtained oil was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (16.9 mg, 30%) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([O-:15])=[O:14]>>[Cl:1][C:2]1[C:3]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1Oc1ncc(C(F)(F)F)cc1Cl
Yield: 63 %

Procedure:
This material was prepared in 63% yield from 3-chloro-2-fluoro-5-trifluoromethylpyridine and 2-nitrophenol following the general procedure outlined in Example 88. The product was isolated as an amber oil which was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH2:10][C@@:9]1([CH3:25])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@:9]1([CH3:25])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@]1(C(=O)OCc2ccccc2)COCC(=O)N1Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: C[C@@]1(C(=O)OCc2ccccc2)COCCN1Cc1ccccc1
Yield: 70.7 %

Procedure:
(S)-benzyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate (3.4 g, 10 mmol) was reacted with a solution of borane in THF (1 mol/L, 20 mL) according to the procedure as described in Example 34, Step B to give the title compound as colorless oil (2.3 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH-].[Na+].C1C=[C:7]([C:9]2[C:23]3C(=C(Br)C([O-])=C(Br)C=3)OC3[C:10]=2C=C(Br)C(C=3Br)=O)[C:6]([C:29]([O-:31])=[O:30])=CC=1.[Na+].[Na+].C(=[S:37])([O-])[O-].[Na+].[Na+]>O>[SH:37][CH:6]([CH2:7][CH:9]([CH3:23])[CH3:10])[C:29]([OH:31])=[O:30]
Reactant: O=C([O-])c1ccccc1-c1c2cc(Br)c(=O)c(Br)c-2oc2c(Br)c([O-])c(Br)cc12
Reactant: [O-]C([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(S)C(=O)O
Reaction time: 24 h
Yield: 34 %

Procedure:
A total of 1.25 g. (6.5 mmoles) of the product prepared above is taken up in 2 ml. of water. Sufficient 1 N sodium hydroxide is added to dissolve the bromo acid. To this mixture, there is added 5 ml. of 40% sodium thiocarbonate and the vessel is closed and allowed to stand at room temperature for 24 hours. At the end of this period, the solution is acidified with 18 N. sulfuric acid, and extracted with 2 10 ml. portions of ethyl ether. The combined extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to approximately half its volume and chromatographed on a silica gel column (2.2×30 cm). The original solution is eluted with 150 ml. of ethyl ether, and the product recovered by evaporation of the solvent in the eluate. The yield is approximately 34%. The Rf values (TLC) are 0.88 and 1.0 on silica gel and cellulose plates (n-butanol/acetic acid/water-12/3/5).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:6]1[O:5][C:4](=[O:7])[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]1[CH3:1]
Reactant: CC1=C(c2ccccc2)C(=O)OC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=C(c2ccccc2)C(=O)OC1Br

Procedure:
2,5-Dihydro-4-methyl-2-oxo-3-phenylfuran, (U.S. Pat. No. 3,622,569), (355 g) in carbon tetrachloride (50 mls) and N-bromosuccinimide (3.85 g) were heated under reflux in the presence of 2,2'-azobisisobutyronitrile (AIBN) (cat.quantity) and a 150W lamp. After 1 h a pale yellow solution was formed accompanied by the presence of succinimide. T.l.c. analysis showed a mixture of products. After filtration, and removal of solvent, the residue was purified by flash chroma-tography on silica gel eluting with 10% ethyl acetate/hexane. The title compound was obtained as a viscous yellow oil, (3.53 g, 68%), (Found; M+, 251.9802. C11H9O2Br requires M, 251.9786); νmax 1780(s) and 1650(w)cm-1 ; δH (CDCl3) 2.28 (3H,s), 6.80 (1H,s) and 7.45 (5H,m).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].CC1C=CC(S(O)(=O)=O)=CC=1.[C:23]1([C:29]2([C:35]([OH:37])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl.Cl>[OH-].[Na+]>[CH2:5]([O:4][C:2]([N:32]1[CH2:31][CH2:30][C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]([OH:37])=[O:36])[CH2:34][CH2:33]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Yield: 94.7 %

Procedure:
Benzyl chloroformate (4.75 mL, 33.1 mmol) was added dropwise to a solution of 4-phenyl-4-piperidinecarboxylic acid p-methylbenzenesulfonate (10.0 g, 26.5 mmol) in 1M sodium hydroxide (200 mL)/dichloromethane (100 mL). After 2 hours the reaction mixture was made acidic with 1M hydrochloric acid (pH=3), the organic layer was separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The organic layers were collected, concentrated and crude product washed with water (3×50 mL) to give 8.52 g of 4-phenyl-piperidine-1,4-dicarboxylic acid monobenzyl ester. LRMS m/z 340.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[O:19]1CC[CH2:21][CH2:20]1.C([N-]C(C)C)(C)C.[Li+].C(=O)C.[Cl-].[NH4+]>C(OCC)C>[OH:19][CH:20]([CH:3]1[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:2]1=[O:1])[CH3:21]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Cl-]
Solvent: CCOCC
Product: CC(O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 479.3 %

Procedure:
tert-Butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate from Procedure 1, Step G (1.2 g, 4.70 mmol) was dried by evaporating with toluene (5 mL) three times in vacuo, dissolved in tetrahydrofuran (50 mL), and cooled to −78° C. To this solution was added lithium diisopropylamide mono(tetrahydrofuran) (6.3 mL, 9.4 mmol, 1.5 M in cyclohexane). The reaction mixture was stirred for 35 min at −78° C. before adding acetaldehyde (0.527 mL, 9.4 mmol). After 10 min, the reaction mixture was diluted with diethyl ether, poured into saturated ammonium chloride, and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6.7 g of a clear oil. The residue was purified by flash chromatography eluting with 20–40% ethyl acetate/hexanes to give the title compound (0.620 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
To a stirred mixture of 76 parts of 4-fluoro-2-nitrobenzoic acid and 225 parts of benzene are added dropwise 71 parts of sulfinyl chloride. Upon completion, stirring is continued first for 5 hours at reflux and further overnight at room temperatue. The reaction mixture is evaporated. The residue is taken up twice in benzene and the latter is evaporated each time, yielding 85 parts of 4-fluoro-2-nitrobenzoyl chloride as a residue.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1
Reactant: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@@H]1CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@@H]2CO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a stirred solution of the ethyl 4-(cis-2-(hydroxyl-methyl)cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (6.4 g, 20.55 mmol) in ethanol (100 mL) was added aqueous sodium hydroxide solution (1 M, 51.4 mL, 51.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Upon completion of reaction as indicated by LCMS and TLC, the reaction mixture was concentrated, diluted with water (100 mL), then neutralized while stirring with aqueous citric acid solution (2 M, 51.4 mL, 103 mmol). The resulting precipitate was filtered, washed with water (2×50 mL) and dried to afford 4-(cis-2-(hydroxymethyl)-cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (5.6 g, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm δ 13.17 (br. s., 1H), 8.71 (d, J=7.42 Hz, 1H), 8.50 (s, 1H), 4.49-4.60 (m, 2H), 3.40-3.46 (m, 3.32-3.39 (m, 2H), 2.47 (s, 3H), 2.22 (sxt, J=6.87 Hz, 1H), 1.95-2.04 (m, 1H), 1.78 (qd, J=4.49, 8.00 Hz, 1H), 1.66-1.72 (m, 1H), 1.49-1.61 (m, 2H). MS (ESI) m/z 284.3 [M+1]+.
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C1([C@@H]([N:24]([C@H:48]([C:50]2[CH:55]=[CH:54]C=CC=2)C)P2OC3C=CC4C=CC=CC=4C=3C3C4C(C=CC=3O2)=CC=CC=4)C)C=CC=CC=1.C1(NC)CC1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCO>[CH:50]1([CH2:48][NH:24][C@H:5]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH:4]=[CH2:3])[CH2:55][CH2:54]1
Reactant: C[C@@H](c1ccccc1)N([C@@H](C)c1ccccc1)p1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1
Reactant: COC(=O)OC/C=C/c1ccc(F)cc1
Agent: CNC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@H](NCC1CC1)c1ccc(F)cc1
Reaction time: 2.5 h
Yield: 851.9 %

Procedure:
A mixture of (2E)-3-(4-fluorophenyl)prop-2-en-1-yl methyl carbonate (420 mg), N,N-bis[(1S)-1-phenylethyl]dinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine (108 mg), [Ir(COD)Cl]2 (27 mg), cyclopropyl methyl amine (374 μL) and EtOH (5 mL) was stirred under refluxing EtOH for 6H under N2. The progress of the reaction was monitered by HPLC. At the end of the reaction, addition of co-solvent (20 ml EtOH and 20 ml THF) and MP-TsOH resin (6 g) and the mixture was allowed to stirred at RT with swilling every 15 mins for 2-3 hours. Filtered the resin and washed the resin with plenty of EtOH, THF, DCM. The resin was taken up in 3.5N NH3 in MeOH (20 mL) and let it stir for overnight. Filtered the resin and washed the resin excessively with EtOH, THF and DCM. Combined the filtrate and evaporated all the solvent. The crude product was purified by flash chromatography (10% EtOAc/Hexane) to afford the title compound as a viscous oil (350 mg, 88%). 1H NMR (300 MHz, CDCl3) revealed branched/linear ratio (9:1) 0.27 (m, 2H), 0.47 (m, 2H), 1.10 (m, 1H), 2.40 (m, 2H), 4.51(m, 1H), 5.25-5.39 (m, 3H), 7.02-7.22 (m, 4H). MS APCI, m/z=206 (M+1). LC/MS 0.85 min., Method A. 94% ee was determined by NMR in the presence of TFAE-d11
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([NH2:15])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].O>COCCOC>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([NH:15][CH2:2][CH2:1][OH:3])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: C1CO1
Reactant: Nc1cc(C(F)(F)F)c(N)cc1[N+](=O)[O-]
Solvent: COCCOC
Solvent: O
Product: Nc1cc(C(F)(F)F)c(NCCO)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Ethylene oxide is passed in portions into a mixture of 2.2 g (10 mmol) of 1,4-diamino-2-nitro-5-trifluoromethylbenzene, 25 ml of water and 10 ml of monoethylene glycol dimethyl ether at 60° C. in the course of 20 minutes, and the reaction is monitored by thin layer chromatography. When the monohydroxyethylation is complete, the mixture is cooled slowly to room temperature and the precipitate is filtered off and washed with water.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:17][C:18]1[C:26]([O:27][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: COc1ccc(-c2nc(CBr)c(C)o2)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a solution of 4-Bromomethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole (0.10 g, 0.35 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.061 g, 0.35 mmol) and potassium carbonate (0.171 g, 1.05 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.117 g, 87%). 1H NMR (DMSO-d6, 400 MHz): δ 2.42 (s, 3H), 3.82 (s, 3H), 5.06 (s, 2H), 7.10 (m, 3H), 7.37 (m, 1H), 7.86 (m, 3H) and 8.13 (br s, 1H). MS ES+ (375.12), HPLC (method I) Rt=15.78 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][NH:24][CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].CO>C(Cl)Cl>[C:35]([N:24]1[CH2:25][CH2:26][C:27]2[N:28]=[C:20]([NH:19][C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:8]4[C:9]5[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=5)[CH2:6][CH2:7]4)[CH2:16][CH2:15]3)=[O:18])[S:21][C:22]=2[CH2:23]1)(=[O:37])[CH3:36]
Reactant: O=C(Nc1nc2c(s1)CNCC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(6-fluoroindolin-1-yl)-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperidine-1-carboxamide, prepared as in Example 19 above (51.6 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added pyridine (0.5 mL) and then acetyl chloride (0.014 mL, 0.2 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 15 min and then MeOH (1 mL) was added. The resulting mixture was continuously stirred for 15 min and concentrated. The resulting residue was purified by column using EtOAc as the eluent to yield N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-(6-fluoroindolin-1-yl)piperidine-1-carboxamide.