Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]#[C:5][C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[Ca+2]>C(OCC)(=O)C.CO>[CH3:1][N:2]([CH3:9])[CH2:3]/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: CN(C)CC#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C/C=C\C(=O)O
Reaction time: 2 h
Yield: 39.4 %

Procedure:
2 g of the compound obtained in step 1) was diluted with 120 ml of a mixed solvent of ethyl acetate and methanol (1:1), and 450 mg of calcium carbonate on palladium was added thereto. The resulting mixture was stirred under a hydrogen gas for two hours. After the reaction terminated, the resulting solution was filtered through a cellite pad and distilled under a reduced pressure. The resulting residue was purified by column chromatography (methylene chloride:methanol=2:1) to obtain the title compound (800 mg, 39%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:17])C.OS(O)(=O)=O>O>[CH2:19]([O:18][CH:16]([CH3:17])[CH2:15][OH:14])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOC(C)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCOC(C)CO
Reaction time: 3 h

Procedure:
2.0 g of LiAlH4 was added to 62 ml of ether and the mixture was stirred for 3 hours. To the mixture was added dropwise 12.7 g of (-)-ethyl-2-butoxypropionate in the same manner as in Example 1, and the mixture was stirred for 15 minutes. Then, 50 ml of water and 50 ml of 10% H2SO4 aqueous solution were added thereto. The ther layer was separated, dried with MgSO4 and filtrated. Ether was distilled off toobtain the objective product at an yield of 7.4 g. The optical rotation [α]D24° was +24.4°.
Reaction SMILES: C(Br)C.[Mg].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[CH:11].[Cl:12][CH2:13][C:14]([C:16]1([Cl:19])[CH2:18][CH2:17]1)=[O:15].[Cl-].[NH4+]>C(OCC)C>[Cl:12][CH2:13][C:14]([C:16]1([Cl:19])[CH2:18][CH2:17]1)([OH:15])[C:11]#[C:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)C1(Cl)CC1
Reactant: C#Cc1cccs1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: OC(C#Cc1cccs1)(CCl)C1(Cl)CC1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
22.2 g (0.203 mole) of ethyl bromide are slowly added to 4.9 g (0.203 mole) of magnesium turnings in 100 ml of diethyl ether. After completion of the addition, the reaction mixture is heated under reflux for 30 minutes and then cooled to room temperature, and a solution of 20 g (0.185 mole) of 2-thienylethine in 50 ml of diethyl ether is subsequently added dropwise with stirring. The mixture is heated under reflux for 1 hour and again cooled to room temperature. 28.3 g (0.185 mole) of 1-chloro-cyclopropyl chloromethyl ketone are added dropwise with stirring and the mixture is then heated under reflux for a further 2 hours. After cooling to room temperature, the reaction mixture is poured into a saturated aqueous ammonium chloride solution and the mixture is extracted three times with diethyl ether. The combined organic phases are washed once with water, dried over sodium sulphate and concentrated under reduced pressure. 47.0 g (97% of theory) of 1-chloro-2-(1-chlorocyclopropyl)-4-(thiophen-2-yl)-but-3-in-2-ol are obtained in this way in the form of an oil which is reacted further without additional purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[N:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[N:43]=[N:42][N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnnn4CC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnnn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-ethyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.45 g) in methylene chloride (13.5 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.12 g) in methylene chloride (9.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-ethyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 242) (221 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]2=O>C(O)C.[Pd]>[OH:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]2[C:7]=1[CH2:6][CH:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4]2
Reactant: CCOC(=O)C1Cc2c(F)ccc(O)c2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1Cc2c(O)ccc(F)c2C1

Procedure:
94 g (0.4 mol) of the compound from Example 26 are hydrogenated in 600 ml of ethanol using 20 g of Pd-C (5% strength) at 30 bar of H2 and 60° C. for 4 h. The catalyst is filtered off, the solution is evaporated and the residue is flash chromatographed on silica gel (eluent: petroleum ether/acetone 5:1). After evaporating the fractions containing the product, the residue is recrystallized from ligroin.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1CO>>[Na:1].[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])[C:13]=1[CH3:30]
Reactant: OCC1OCCCO1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCC2OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 10 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,3-dioxan-2-ylmethanol obtained in the step (32b) to obtain the title compound (148 mg, total yield: 10%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:24][C:23](=[O:25])[C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:32][CH2:33][CH:28]([NH:27][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C:6]2[C:5]4[C:23](=[O:25])[CH2:24][C:2]([CH3:26])([CH3:1])[CH2:3][C:4]=4[O:8][CH:7]=2)[CH:19]=[CH:18][CH:17]=3)=[O:21])[CH2:29][CH2:30]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: CC1(C)CC(=O)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2C1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6c5C(=O)CC(C)(C)C6)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 16 g and amine 14.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[C:5]([NH:8][C:9](=[O:22])[CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:21])[S:6][CH:7]=1)#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:29]>CO.C(Cl)Cl>[C:1]([C:3]1[C:4]([C:23]2[N:27]=[CH:26][N:25]([CH3:29])[N:24]=2)=[C:5]([NH:8][C:9](=[O:22])[CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:21])[S:6][CH:7]=1)#[N:2]
Reactant: N#Cc1csc(NC(=O)CN2C(=O)CCc3ncccc32)c1-c1nc[nH]n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: Cn1cnc(-c2c(C#N)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1
Reaction time: 4 h

Procedure:
N-(4-cyano-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (180 mg, 0.475 mmol) was dissolved in MeOH/CH2Cl2 (1:1, 4 mL total), and TMSCHN2 (Aldrich, 2.0 M in diethyl ether, 8 mL, 16 mmol) was added at rt. This was stirred for 4 h, whereupon the reaction mixture was concentrated under reduced pressure. The crude residue was purified by HPLC to give a white solid as a trifluoroacetic acid salt: method [11], retention time=7.56 min; MS (ESI) 394.2 (MH+); 1H NMR (300 MHz, CD3OD) 8.41 (s, 1H), 8.25 (d, J=5.0 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.52-7.42 (m, 1H), 4.98 (s, 2H), 3.97 (s, 3H), 3.40-3.20 (m, 2H), 2.96 (t, J=8.3 Hz, 2H).
Reaction SMILES: O[C@@H:2]([CH3:19])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C@H:3]1[C:4](=[O:6])[O:5][C@H:2]1[CH3:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.1 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-(phenethyloxycarbonylamino)-butanoic acid (0.35 g, 1.30 mmol) in dry CH2Cl2 (35 mL), Et3N (0.54 mL, 3.90 mmol) and subsequently TBTU (0.50 g, 1.56 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.185 g, 57%) as white solid. MS (ESI) m/z: 250 [M−H]+; (ESI) m/z: 249 [M−H]−. 1H NMR (DMSO-d6): δ 1.33 (d, J=6.3 Hz, 3H), 2.89 (t, J=6.8 Hz, 2H), 4.15-4.29 (m, 2H), 4.84 (dq, J=6.3 Hz, 1H), 5.40 (dd, J=6.1, 9.4 Hz, 1H), 7.19-7.36 (m, 5H), 8.23 (d, J=9.4 Hz, 1H).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.17 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.16 g, 47% yield), mp=87–89° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=−23.1° (c=1, EtOH).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([CH2:9][CH3:10])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([I:20])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: [I-]
Reactant: CCc1cc(Br)ccc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCc1cc(Br)ccc1I
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred mixture of 4-bromo-2-ethylaniline (80 g, 0.4 mol) in distilled water (400 ml) is added concentrated sulphuric acid (80 ml), followed by brief heating to 60° C. for 1 hour until dissolution is complete. The mixture is allowed to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (28 g, 0.4 mol) in distilled water (140 ml) dropwise over 15 minutes, maintaining the temperature below 5° C., followed by additional stirring for 30 minutes. The reaction mixture is allowed to come to room temperature and then a solution of aqueous potassium iodide (199 g, 1.2 mol) in distilled water (200 ml) is added dropwise at room temperature. After the addition is complete the solution is briefly heated to 80° C. then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (1000 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (500 ml) and aqueous sodium thiosulfate (2×250 ml). The organic phase is dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethyl-1-iodobenzene (84.6 g) as an orange liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:22]3[CH:27]=[C:26]([C:28](=[O:33])[NH:29][CH:30]4[CH2:32][CH2:31]4)[CH:25]=[CH:24][C:23]=3[CH3:34])[CH:14]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C.O>CO>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:22]3[CH:27]=[C:26]([C:28](=[O:33])[NH:29][CH:30]4[CH2:31][CH2:32]4)[CH:25]=[CH:24][C:23]=3[CH3:34])[CH:14]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
A mixture of the product of step ii) (0.88 g) and 5N sodium hydroxide (2.3 mL) in methanol (20 mL) was heated at 50° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was treated with glacial acetic acid (1 mL) and then water (20 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to afford the sub-title compound (0.77 g).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:16][C:17]([C@H:19]2[CH2:21][C@@H:20]2[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:14][OH:15])=[C:9]([O:27][CH3:28])[CH:8]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:15][CH2:14][C@H:13]([NH:16][C:17]([C@H:19]1[CH2:21][C@@H:20]1[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][C:9]=1[O:27][CH3:28]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1[C@H](CO)NC(=O)[C@H]1C[C@@H]1c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(O)ccc1[C@H](CO)NC(=O)[C@H]1C[C@@H]1c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid {(R)-1-[4-(tert-butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-2-hydroxy-ethyl}-amide (393.4 mg, 0.88 mmol) dissolved in 20 ml THF at 0° C., was added 1.32 ml TBAF (1.0 M solution, 1.32 mmol). The ice bath was remove and stirred for 2 hr at rt. It was diluted with ether and quenched with aq. NH4Cl. The organic layer was washed with water and brine, and then dried over MgSO4. It was concentrated and purified on flash column (6% MeOH in DCM) to obtain the titled compound (used directly for next reaction).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH2:23]1
Reactant: BrCC1COc2ccccc2O1
Reactant: COc1ccccc1C1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1
Temperature: 130 °C
Yield: 23.6 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15 mmol), 3-(2-methoxyphenyl)piperidine HCl (38 mg, 0.165 mmol) and triethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 110-150° C. for 90 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 12 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[OH:14][CH:3]1[CH:4]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)[CH2:26][CH2:27]2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-(4-nitro-phenyl)-piperazine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH:9]=1)/[CH:7]=[N:18]/[OH:19]
Reactant: NO
Reactant: Cc1cc(Br)cc(C=O)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)cc(/C=N/O)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol (50.0 mL) were added sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated on rotavapour to obtain crude compound, which was washed with water filtered and dried under vacuum to afford the title compound as a white solid: mp 126-127° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[N:5]=[CH:4][CH:3]=1.[I-].[Na+].Cl[Si](C)(C)C.O>CC#N.CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][NH:5][C:6](=[O:10])[C:7]=1[CH:8]=[O:9]
Reactant: COc1nccc(I)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1c(I)cc[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A mixture of 4-iodo-2-methoxynicotinaldehyde (25 g, 83 mmol) and sodium iodide (37.0 g, 249 mmol) in MeCN (500 mL) was treated drop-wise with chlorotrimethylsilane (31.4 mL, 249 mmol) over 15 minutes. The reaction mixture was stirred at RT for 2 h, then to dryness. The residue was suspended in EtOAc, water, and satd. NaHCO3, the solid collected via filtration, triturated with MeCN and dried to afford 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (12 g, 51%) as a yellow solid. MS (ESI) m/z: 250.0 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:16]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:38]1N=C(N2CCOC[C@@H]2C)C2CN(C(OC(C)(C)C)=O)CC=2N=1>>[CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][C@@H:34]4[CH3:38])[C:16]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)OC(C)(C)C)C2

Procedure:
Method as described for tert-Butyl 2-(4-(3-cyclopropylureido)-2-fluorophenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 143) using (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 1).
Reaction SMILES: [NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6](N[C@@H]2CCN(C)C2)=[O:7])=[C:4]([F:18])[CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]1>>[NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 229, on a 5.77 mmol scale utilising 4-amino-1-ethylpiperidine (Fluorochem; 815 mg, 6.35 mmol), as an orange solid (1.23 g, 75%)
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:3]1.[ClH:15].[CH2:16]([OH:18])[CH3:17]>>[ClH:15].[CH2:16]([O:18][C:8]([C:7]1[CH2:2][NH:3][C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:6]=1)=[NH:9])[CH3:17]
Reactant: CCO
Reactant: CC(C)(C)Cc1ccc(C#N)c(=O)[nH]1
Agent: Cl
Product: CCOC(=N)C1=CC=C(CC(C)(C)C)NC1
Reaction time: 2 h

Procedure:
A solution of 1,2-dihydro-2-oxo-6-neopentyl-3-cyanopyridine (8.8 g) and 400 ml of absolute ethanol is cooled in an ice bath and a slow stream of anhydrous hydrogen chloride is passed therethrough for 2 hr. The resulting solution is allowed to stand at ambient temperature for 3 days. Thereafter the solvent is evaporated under reduced pressure at ambient temperature, and the resulting material dissolved in warm trichloromethane. Acetone is added and following cooling the material is recovered by filtration and washed with acetone, yielding ethyl-1,2-dihydro-6-neopentyl-3-pyridine-carboximidate hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([O:15]C)=[O:14])[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Reaction time: 5 h
Yield: 97.5 %

Procedure:
Methyl 5-oxo-1-phenylprolinate (0.078 g, 0.36 mmol) was combined with 2N aqueous sodium hydroxide (2 ml) in ethanol (2 ml) at 0° C. The mixture was stirred at between −10° C. and 0° C. for 5 hours. The solvent was then evaporated in vacuo and the residue was acidified to pH1 by the addition of 2M aqueous hydrogen chloride. To this was added dichloromethane and the mixture was passed through a phase separator. The aqueous layer was washed with more dichloromethane and then the combined dichloromethane layers were evaporated to give 5-oxo-1-phenyl-proline (0.072 g) as a yellow gum which was used without further purification in the next step.