Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][N:27]=[N+:28]=[N-:29])[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)C=CO[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)C=CO[C@@H]1CN=[N+]=[N-]
Reaction time: 24 h

Procedure:
3,4-Di-O-acetyl-1,2-dideoxy-6-O-tosyl-D-arabinohex-1-enopyranose (50g.) was dissolved in hexamethylphosphoramide (800 ml.) and sodium azide (34 g.) was added and the solution was stirred at 25° for 24 hours. The hexamethylphosphoramide was distilled off under high vacuum and the residue was taken up in chloroform and washed with water. The chloroform extract was dried (MgSO4), filtered and evaporated to give a crude gum which was chromatographed on a silica gel column (150 × 7.5 cm.) using 7% acetone in hexane as the eluent to give 3,4-di-O-acetyl-6-azido-1,2,6-trideoxy-D-arabinohex-1-enopyranose (25 g.) as a colorless gum, (Found: C, 47.23; H, 5.30; N, 16.37. C10N13N3O5 requires: C, 47.06; H, 5.13; N, 16.46%), [α]D26 × 25.1° (CH3OH), νmax (CHCl3) 2110, 1755, 1660, 1220, 1040 cm. -1, δ(CDCl3) 2.06, 2.09 (6H, s, OAc), 4.91 (1H, ddd, J = 6.5Hz, 3.0Hz, 1Hz, H2), and 6.53 ppm. (1H, dd, J = 6.5Hz, 1.5Hz, H1).
Reaction SMILES: C(OC1[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][CH2:21][CH:22]=[CH2:23])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH2:48]([Cl:50])Cl>[Zn+2].[Br-].[Br-]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][CH2:21][CH:22]=[CH2:23])[C@@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:42][C@@H:48]1[Cl:50])(=[O:10])[CH3:9]
Reactant: ClCCl
Reactant: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)C(OC(C)=O)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [Zn+2]
Product: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](Cl)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 11.7 %

Procedure:
To a solution of 2 (3.5 g, 5.17 mmol) in CH2Cl2 (10 mL) Cl2CHOCH3 (0.56 mL, 6.2 mmol) and ZnBr2 (100mg) were added under an Ar atmosphere. The mixture was stirred for 1 h, then concentrated and the residue was chromatographed on silica gel with pentane-EtOAc (6:4) to give 3 (396 mg, 85%), [α]D+93.4° (c 1.2, CHCl3); 1H NMR (CDCl3) δ 6.22 (s, 1H, J1,2=3.9 Hz, H-1), 5.80 (m, 1H, Hc), 5.56 (t, 1H, J3,4 and J2,3≈9.7 Hz, H-3), 5.31 (dd, 1H, J4′,3′=3.5 Hz, J4′,5′=0.8 Hz, H-4′), 5.20 (1H, Hb), 5.12 (1H, Ha), 4.93 (dd, 1H, H-2),4.86(dd, 1H, J2′,3′=10.2 Hz, H-3′), 4.58 (dd, 1H, J6a,6b=12.1 Hz, J5,6a=0.7 Hz, H-6a), 4.34 (d, 1H, J1′,2′=7.7 Hz, H-1), 4.29 (dd, 1H, J5,6b =4.2 Hz, H-6B),4.25-4.01 (m, 5H, Hd, He, H-5, H-6′a, H-6′b), 3.85-3.78 (m, 2H, H-4, H-5′), 3.42 (dd, 1H, H-2′). Calc'd for C27H37Cl16 (653.025) C, 49.66; H, 5.71, Cl, 5.43. Found C, 49.68, H, 5.68, Cl, 5.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: BrCc1ccncc1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccncc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 0.5 mmol), 4-bromomethyl-pyridine (98 mg, 0.6 mmol) and Cs2CO3 (245 mg, 0.75 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as little yellow solid (140 mg, 76%). LC/MS m/e calcd. for C22H17ClN2O: 360, observed (M+H)+: 361.2 1HNMR (400 MHz, MeOD-d4) δppm 2.22-2.37 (m, 2 H) 3.32-3.40 (m, 1 H) 5.39 (s, 2 H) 6.15 (d, J=7.58 Hz, 1 H) 6.74-6.85 (m, 1 H) 6.92 (d, J=7.83 Hz, 1 H) 7.10-7.19 (m, 1 H) 7.24-7.42 (m, 4 H) 7.93 (d, J=6.32 Hz, 2 H) 8.80 (d, J=6.06 Hz, 2 H). MS calcd. for C22H17ClN2O 360, obsd. (ESI+) [(M+H)+] 361.1.
Reaction SMILES: [Si]([O:8][C@:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH:17]=2)[CH2:14][CH2:13][O:12][C@@H:11]([CH3:15])[CH2:10]1)(C(C)(C)C)(C)C.[CH2:34](Cl)[CH:35]=[CH2:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:36]([N:29]1[C:30]2[C:25](=[CH:24][C:23]([S:22][C:18]3[CH:17]=[C:16]([C@@:9]4([OH:8])[CH2:14][CH2:13][O:12][C@@H:11]([CH3:15])[CH2:10]4)[CH:21]=[CH:20][CH:19]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:27][C:28]1=[O:33])[CH:35]=[CH2:34]
Reactant: C[C@H]1C[C@@](O[Si](C)(C)C(C)(C)C)(c2cccc(Sc3ccc4c(c3)CCC(=O)N4)c2)CCO1
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=CCN1C(=O)CCc2cc(Sc3cccc([C@@]4(O)CCO[C@@H](C)C4)c3)ccc21
Yield: 86 %

Procedure:
Using an analogous procedure to that described in Example 18, (2S,4R)-4-(tert-butyldimethylsilyloxy)-2-methyl-4-[3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran was reacted with allyl chloride and the resultant product was treated with tetrabutylammonium fluoride to give (2S,4R)-4-[3-(1-allyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 86% yield, m.p. 107°-109° C. (recrystallised from diethyl ether);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5]C(C)=[CH:7][CH:8]=1.[O-][Mn](=O)(=O)=O.[K+].CC[O:21][C:22]([CH3:24])=[O:23]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:24]([C:22]([OH:21])=[O:23])=[N:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C(=O)O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-methoxy-6-methyl-2-nitropyridine (7 g, 0.041 mol) in water (140.0 mL) was added KMnO4 (32.88 g, 0.208 mol, S.d. fine chemicals, India) at 80° C. The reaction mixture was stirred for 16 h at 100° C. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was filtered and the solids were washed with water. The filtrate was acidified and extracted with EtOAc (500 mL×2). The organic layers were then dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 13.6 (br. s., 1H), 8.39 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.06 (s, 3H). MS (ESI, positive ion) m/z: 199 (M+H).
Reaction SMILES: [C:1]([S:26]([NH:29][CH2:30][CH3:31])(=[O:28])=[O:27])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].C(N(CC)CC)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH:54]=[CH2:55]>C1(C)C=CC=CC=1>[C:1]([S:26]([N:29]([CH2:55][CH2:54][C:53]([O:57][CH2:58][CH3:59])=[O:56])[CH2:30][CH3:31])(=[O:27])=[O:28])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:24])([F:25])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: C=CC(=O)OCC
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 97 °C
Yield: 97 %

Procedure:
In a 1-L, three-necked flask, fitted with a condenser, stirrer, and thermometer were placed 263 g (0.5 mole) of C8F17SO2N(C2H5)H, 15 g of triethylamine, 3 g of phenothiazine, 150 g toluene and 90 g (0.9 mole) of ethyl acrylate. The reaction mixture was stirred and heated at reflux (about 97° C.) for 16 hours to yield the known adduct C8F17SO2N(C2H5)C2H4COOC2H5 in 97% yield as shown by H-NMR analysis. The adduct was isolated by stripping off the toluene solvent, triethyl amine and excess ethyl acrylate under water aspirator pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].[Br:16]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(C(=O)OC)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1ccccc1CBr
Temperature: 90 °C
Yield: 97.3 %

Procedure:
20.6 g of the methyl α-(2-methylphenyl)-β-methoxyacrylate obtained as described in Method A, 17.65 g of N-bromosuccinimide, 0.2 g of azobisisobutyronitrile and 150 ml of CCl4 are slowly heated to 90° C. and kept at this temperature until all of the succinimide floats on the solvent. The mixture is filtered, the filtrate is evaporated down, the remaining oil is dissolved in about 5 ml of acetone and the solution is brought to crystallization with n-hexane. 27.5 g of colorless crystals of melting point 86°-87° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5])=[O:17]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N#Cc1c(F)cc(Cl)cc1Br
Product: N#Cc1c(F)cc(Cl)cc1C(=O)c1cccc(Br)c1
Yield: 55 %

Procedure:
The title compound was synthesized as described for Example 64i in 55% yield starting from 2-bromo-4-chloro-6-fluorobenzonitrile (6.35 g, 27.08 mmol) and 3-bromobenzoyl chloride (3.58 mL, 27.08 mmol).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:8]=1[NH:16][C:17](=[O:38])[CH2:18][N:19]1[C:23](=[O:24])[C:22]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:21]([C:30]2[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=2)[C:20]1=[O:37])([CH3:6])[CH3:5]>O1CCCC1.C(OCC)(=O)C.[Cu](I)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>[C:1]([C:33]1[CH:34]=[CH:35][C:30]([N:21]2[C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:23](=[O:24])[N:19]([CH2:18][C:17]([NH:16][C:8]3[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=3[CH:4]([CH3:6])[CH3:5])=[O:38])[C:20]2=[O:37])=[CH:31][CH:32]=1)#[N:2]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(I)cc2)C2(CCCCC2)C1=O
Reactant: [C-]#N
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(C#N)cc2)C2(CCCCC2)C1=O
Temperature: 80 °C

Procedure:
38 mg (0.58 mmol, 2 eq.) of potassium cyanide and 5.5 mg (0.029 mmol, 0.1 eq.) of copper iodide are added to 170 mg (0.29 mmol, 1 eq.) of N-(2,6-diisopropyl-phenyl)-2-[1-(4-iodo-phenyl)-2,4-dioxo-1,3-diaza-spiro[4.5]dec-3-yl]acetamide in 10 ml of tetrahydrofuran. The reaction medium is degassed with nitrogen for 20 minutes, and 17 mg (0.015 μmol, 0.05 eq.) of tetrakis(triphenylphosphine)palladium are added. The medium is heated at 80° C. for 6 hours. The medium is cooled to room temperature and diluted with ethyl acetate, and then filtered through Celite. The filtrate is washed with water. The organic phases are combined. They are dried over sodium sulfate. The solvents are evaporated off and the residue is precipitated from dichloromethane and heptane. The product 2-[1-(4-cyanophenyl)-2,4-dioxo-1,3-diaza-spiro[4.5]dec-3-yl]-N-(2,6-diisopropylphenyl)acetamide is obtained in the form of a white solid.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[CH2:18]([NH2:20])[CH3:19].[OH-].[Na+]>>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][NH:20][CH2:18][CH3:19])[CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1CCOC1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A mixture comprising 4.09g of (tetrahydro-3 -furanyl)methyl tosylate, 17 ml of 70% aqueous ethylamine solution and 8.2 ml of 2 N aqueous sodium hydroxide solution was stirred at 75° C. for 6 hours. The reaction fluid was concentrated under a reduced pressure to obtain crude N-{(tetrahydro-3-furanyl)methyl}-N-ethylamine. To this were added 2.00 g of 1,1-bis(methylthio)-2-nitroethylene and 20 ml of acetonitrile. The resulting mixture was refluxed for 3 hours. The reaction fluid was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/2) to obtain 0.81 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-ethylamino]-1-methylthio-2-nitroethylene.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(COCc2ccccc2)n1Cc1ccc2c(c1)OCO2

Procedure:
To a solution (2.5 ml) of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) in THF was added sodium hydride (26 mg) at 0° C. with stirring. The mixture was stirred at room temperature for 10 min., benzylbromide (71 μl) was added, and the mixture was further stirred for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (210 mg) as colorless crystals.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1>C1(C)C=CC=CC=1.CCOCC>[CH2:11]1[C:12]2[N:8]([C:7]([C:1]([Cl:4])=[O:2])=[CH:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: c1cc2n(c1)CCC2
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2n1CCC2
Temperature: 25 °C

Procedure:
To a stirred, ice-bath cooled portion (30 ml) of 12.5% phosgene in toluene was added a solution of 2,3-dihydro-1H-pyrrolizine (0.80 g, 0.0074 m) in ether (30 ml) dropwise over ca two minutes. After stirring cold for ca 2.5 hr, the reaction mixture is allowed to warm to room temperature, the volatiles are removed in vacuo, and the resultant crystalline 2,3-dihydro-1H-pyrrolizine-5-carbonyl chloride used as is in the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[Cl:1][CH2:2][C:3]1[O:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[N:5]=1
Reactant: CC(C)(NC(=O)CCl)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)N=C(CCl)OC1=O
Temperature: 25 °C

Procedure:
To stirring mixture of 2-(2-chloro acetylamino)-2-methyl propionic acid (18.04 g, 0.10 mol), triethylamine (11.13 g, 0.11 mol), and 100 mL of acetone cooled with an ice bath was added ethyl chloroformate (10.52 mL, 0.11 mol) over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. Hexane (200 mL) was added to the residue and the mixture was filtered. After removal of the solvent under vacuum, the residue was distilled under reduced pressure (bp 59-60° C. at 7 mmHg) to give a colorless oil. A yield of 13.18 g (82%) was obtained.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:6]=[C:7]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:24])=[C:20](Cl)[N:21]=3)[C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14]2)[C:8]([F:12])=[CH:9][C:10]=1[F:11].Cl.Cl.[NH2:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[NH2:31][CH:32]1[CH2:35][N:34]([C:20]2[N:21]=[C:22]3[C:17]([C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14][N:13]3[C:7]3[C:8]([F:12])=[CH:9][C:10]([F:11])=[C:5]([NH2:4])[CH:6]=3)=[CH:18][C:19]=2[F:24])[CH2:33]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Reactant: NC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To 200 ml of acetonitrile were added 3.7 g of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 2.18 g of 3-aminoazetidine dihydrochloride, and 6.06 g of triethylamine. The solution was stirred at 80° C. for 15 hours. The reaction solution was cooled whereupon the precipitated solid was collected by filtration and washed with ethanol and isopropyl ether to give 3.7 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=1[NH2:11].[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[Cl:17][CH2:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[OH:8])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 26 °C
Yield: 73.6 %

Procedure:
95 ml of triethylamine (0.674 mol) were added to a solution of 83 g of 2-hydroxy-4-methylaniline (0.674 mol) in 2.5 liters of tetrahydrofuran, with stirring and under an inert atmosphere, followed, after 30 minutes, by dropwise addition of a solution of 54 ml of chloroacetyl chloride (0.678 mol) in 60 ml of tetrahydrofuran, while maintaining the temperature at 25-27° C. The reaction medium was stirred at room temperature for 4 hours, filtered through a sinter funnel and the inorganic salts were rinsed with 500 ml of tetrahydrofuran. The combined organic phases were poured into 3 liters of ice-cold water with stirring. The precipitate formed was spin-filtered, washed with twice 600 ml of water and once with pentane, and dried under vacuum to constant weight, to give 99 g of 2-chloro-N-(2-hydroxy-4-methylphenyl)acetamide in the form of a beige-coloured powder, in a yield of 74%.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH:16][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)c1cccn1N
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)c1cccn1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
Sodium cyanoborohydride (2.29 g, 36.4 mmol) was added to a solution of 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 3.03 g, 18.2 mmol), 4-fluorobenzaldehyde (1.96 mL, 18.3 mmol) and acetic acid (6 mL), in methanol (120 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo to a volume of about 30 mL. The remaining liquid was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and a 1:1 mixture of ethyl acetate and hexanes (2×200 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→40% ethyl acetate in hexanes) afforded the desired product, 1-(4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid allyl ester (1.87 g, 6.8 mmol, 37% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ: 4.08 (2H, d, J=5.4 Hz), 4.75-4.77 (1H, m), 5.27-5.30 (1H, m), 5.37-5.41 (1H, m), 5.95-5.97 (1H, m), 5.98-6.05 (1H, m), 6.58-6.61 (1H, m), 6.75-6.76 (1H, m), 6.89-6.91 (1H, m), 6.97-7.01 (2H, m), 7.22-7.25 (2H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:31])([F:32])[F:30])(=[O:4])=[O:3]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Methanesulphonyl chloride (2.65 g) was added dropwise to a solution of 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6.7 g) and diisopropylethylamine (9.7 ml) in NMP (40 ml). The mixture was stirred at room temperature for 3 hours. After adding ice (100 g), solid product was collected by filtration, washed with cold ethanol (20 ml) to give 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy]propyl methane-sulfonate (7.4 g). 1H NMR (DMSO) δ: 8.69 (s, 1H), 8.62 (s, 1H), 8.45 (d, 1H), 8.41 (s, 1H), 7.47 (d, 1H), 4.40 (t, 1H), 4.32 (t, 2H), 3.99 (s, 3H), 3.18 (s, 3H), 2.21 (tt, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.INC(=O)CCC(N)=O.[NH2:25][C:26]([NH2:28])=[S:27]>C(OCC)(=O)C.CO>[NH2:28][C:26]1[S:27][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)[N:25]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1cnc(Cl)cn1
Agent: NC(=O)CCC(=O)NI
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1sc(N)nc1-c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
Ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate (Intermediate 45, 2.0 g, 8.77 mM) was dissolved in ethyl acetate (30 mL), to this amberlyst resin (2.0 g) and N-iodosuccinamide (2.1 g, 9.64 mM) were added and stirred for 1 h at room temperature. The resin was filtered and the filtrate was concentrated under reduced pressure to afford crude compound, which was dissolved in methanol (25 mL). Thiourea (0.99 g, 13.15 mM) was added to the reaction mixture and the reaction mixture was heated to reflux for 2 h. The methanol was concentrated under reduced pressure and the resulting residue was partitioned between sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure to obtain crude compound which was purified by flash column chromatography (gradient up to 50% of ethyl acetate/pet ether) to afford 500 mg (20.06%) of ethyl 2-amino-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate off-white solid.