Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](C1C=CC(N)=NC=1)[CH3:2].C(=S)=S.[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([S-:24])=[S:23])=[N:19][CH:20]=1)[CH3:14].C([NH+](CC)CC)C.C(I)C>C(#N)C.C(N(CC)CC)C>[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([S:24][CH2:1][CH3:2])=[S:23])=[N:19][CH:20]=1)[CH3:14]
Reactant: CCc1ccc(NC(=S)[S-])nc1
Reactant: CCc1ccc(N)nc1
Agent: CC[NH+](CC)CC
Solvent: CCI
Solvent: S=C=S
Solvent: CC#N
Product: CCSC(=S)Nc1ccc(CC)cn1

Procedure:
Following a procedure similar to that described in Example 1 above, 5-ethyl-2-aminopyridine [Ban et al., Chem. Ind. (London) 1964 (17), 710-711] is reacted with carbon disulfide and triethylamine in acetonitrile and the resulting triethylammonium (5-ethyl-2-pyridyl)carbamodithioate rected with ethyl iodide to give ethyl (5-ethyl-2-pyridyl)carbamodithioate.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1ccc(NC(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 56 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (150 mg, 0.36 mmol) was reacted with benzenesulfonyl chloride to yield 112 mg (56%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:20]([C:17]2[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:23])[CH:16]=2)=[O:22])[CH2:26][CH2:27]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC2CCOCC2)[nH]n1
Yield: 28 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using 4-aminotetrahydropyran instead of 2-hydroxy-2-methylpropylamine, to the title compound (9.1 mg, 28%) which was obtained as an off white solid. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32][C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:30][CH:31]=3)=[N:20][O:21]C(C)(OC)C)[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55].O>CC(C)=O.Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32][C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[S:30][CH:31]=3)=[N:20][OH:21])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CCNCC
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1

Procedure:
A solution of 7.6 g of the syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate in 30 ml of acetone and 10 ml of 2 N hydrochloric acid was stirred for 40 minutes at room temperature and then 20 ml of water were added thereto. The acetone was evaporated at 30° C. under reduced pressure and 25 ml of ethyl acetate were added thereto. The mixture was decanted and re-extracted and the organic phase was washed with water, dried and vacuum filtered. 1 ml of diethylamine was added to the filtrate and the mixture was triturated and iced. The mixture was vacuum filtered and the recovered product was washed with ether to obtain 6 g of pure syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:9]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=4)[O:21][C:20]3=[O:39])=[N:10][C:11]([N:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)[CH:7]=1.[I:42]CI.N(OCCC(C)C)=O>C1(C)C=CC=CC=1>[N:14]1([C:11]2[N:10]=[C:9]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([C:35]([F:37])([F:38])[F:36])[CH:26]=4)[O:21][C:20]3=[O:39])[C:8]([C:6]3[CH:7]=[C:2]([I:42])[CH:3]=[CH:4][C:5]=3[O:40][CH3:41])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(N)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: Cc1ccccc1
Product: COc1ccc(I)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (4S,5R)-3-{[3-(5-amino-2-methoxyphenyl)-6-azetidin-1-ylpyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (460 mg, 0.792 mmol) in toluene (7 mL) and diiodomethane (2 mL, 24.79 mmol) was added isoamyl nitrite (0.213 mL, 1.585 mmol) dropwise at room temperature. The mixture was stirred at 25° C. for 15 min. Then the mixture was heated at 80° C. for 45 min. The reaction mixture was loaded on a silica column directly and was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 270 mL, gradient to 35% EtOAc in hexanes over 972 mL) to afford (4S,5R)-3-{[6-azetidin-1-yl-3-(5-iodo-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=691.1. found=692.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H); 7.75 (s, 2H); 7.62 (dd, J=8.7, 2.2 Hz, 1H); 7.54-7.38 (m, 1H); 7.29 (d, J=8.3 Hz, 1H); 6.74 (d, J=8.7 Hz, 1H); 6.28 (d, J=8.3 Hz, 1H); 5.75-5.30 (m, 1H); 4.81 (d, J=16.3 Hz, 1H); 4.21-4.00 (m, 6H); 3.79 (s, 3H); 2.48-2.38 (m, 2H); 0.67 (s, br, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:11][CH2:12][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][OH:15].[Cl-].[NH4+]>CN(C=O)C>[CH2:3]([O:11][CH2:12][C:13]([CH2:18][O:19][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH2:16][O:17][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: OCC(CO)(CO)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: OCC(COCc1ccccc1)(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 37.5 %

Procedure:
Sodium hydride (440 mg, 11.01 mmol) and benzyl bromide (1.3 mL, 11.01 mmol) were added to 20 mL of a solution of pentaerythritol (500 mg, 3.67 mmol) in DMF, and the mixture was stirred at room temperature for 14 hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 3-benzyloxy-2,2-bis(benzyloxymethyl)propan-1-ol (560 mg, 38%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][OH:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][O:12][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CC(=O)Cl
Product: C[C@H](COC(=O)c1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure of example 47A, but replacing N-(tert-butoxycarbonyl)-L-alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with benzoyl chloride, provided N-(tert-butoxycarbonyl)-O-benzoyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(Cl)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (25%); 1H NMR (d6-DMSO) δ 12.36 (s, 1H), 7.88–7.76 (m, 3H), 7.63 (t, J=8.1 Hz, 1H), 7.42–7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 527 (M−H−).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Br:19]Br>CC(O)=O>[Br:19][C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(Br)oc2ccc(C=C3SC(=O)NC3=O)cc12
Temperature: 25 °C
Yield: 66 %

Procedure:
In a 25 ml 3 neck flask was placed 5-(3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione (100 mg, 0.39 mmol) (example 68) and Br2 (20 ul, 1 eq.) in 2 ml of AcOH at 0° C. The mixture was allowed to warm to room temperature. After 2 h at room temperature another equivalent of Br2 was added. After 3 h the reaction was filtered off to obtain a yellow product being the title compound (87 mg, 66%).
Reaction SMILES: Br[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5].[Mg].[CH2:10]([O:17][CH2:18][CH2:19][C:20]([CH3:34])([CH3:33])[CH2:21][C@H:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][CH2:18][CH2:19][C:20]([CH3:34])([CH3:33])[CH2:21][C@H:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:23]([OH:24])[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C=CC(CBr)C(C)C
Agent: [Mg]
Product: C=CC(C[C@H](O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
88.5 g of 1-bromo-2(R,S)-isopropyl-3-butene, 13 g of magnesium powder and 41.9 g of 6-benzyloxy-2(S)-tert-butoxycarbonylamino-4,4-dimethyl-hexanal are reacted in a manner analogous to that described in Example 37f). Purification is carried out by FC over 1 kg of silica gel (mobile phases G and E): Rf (3:1 mixture of toluene and ethyl acetate)=0.47; Rt (I)=33.8/34.2 min; FAB-MS: (M+H)+ =520.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCN(C[C@H](N)c2ccccc2)CC1
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To a solution of 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate in 1.5 mL of dichloromethane was added 0.7 mL of trifluoroacetic acid, followed by stirring for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium carbonate solution and a chloroform-methanol mixed solution were added thereto in this order to carry out a layer separation operation. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 120 mg of ethyl 1-[(2R)-2-amino-2-phenylethyl]piperidine-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([CH:58]([NH2:60])[CH3:59])=[N:57][C:53]=2[CH:52]=1>CN(C)C=O.C(OCC)(=O)C.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:60][CH:58]([C:56]1[NH:55][C:54]2[CH:61]=[CH:62][C:51]([C:50]([F:64])([F:63])[F:49])=[CH:52][C:53]=2[N:57]=1)[CH3:59])=[O:7]
Reactant: CC(N)c1nc2cc(C(F)(F)F)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(C)c2nc3cc(C(F)(F)F)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 10d from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-trifluoromethyl-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 90 mg (47% of theory); Rf value: 0.38 (silica gel; ethyl acetate/ethanol=9:1); C23H23F4N3O2 (444.46); mass spectrum: (M+H)+=445
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][C:25]([CH3:27])=[N:24][C:23]=5[CH:28]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:27][C:25]1[O:26][C:22]2[CH:21]=[C:20]3[C:10]4([CH2:17][O:18][C:19]3=[CH:28][C:23]=2[N:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]4=[O:29]
Reactant: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 242-244° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.20 (br s, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.30-7.24 (m, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.99-6.93 (m, 1H), 6.96 (d, J=7.8 Hz, 1H), 5.96 (d, J=6.0 Hz, 1H), 5.42 (d, J=5.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ176.2, 165.2, 151.4, 146.1, 142.0, 138.2, 130.6, 130.1, 125.0, 123.1, 114.3, 111.5, 110.9, 88.4, 76.3, 14.6; MS (ES+) m/z 331.1 (M+39).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]([OH:25])[CH2:23][CH3:24])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CCC(O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(=O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution 1-(3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)propan-1-ol (13 mg, 0.015 mmol) in DCM (3 mL), was added TEA (0.011 ml, 0.079 mmol) and Dess-Martin periodinane (40 mg, 0.094 mmol). After stirring at rt for 10 min, the reaction was quenched with Na2SO3(aq), extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 1-(3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)propan-1-one (4 mg, 74%). LCMS (method A): [MH]+=338, tR=5.08 min.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[C:20]2[N:19]=[C:18]([C:21](O)=[O:22])[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:36])[C:20]2[N:19]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (0.83 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A79. A solution of 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (256.9 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B79. Solution B79 was added to Solution A79 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-amide (98.7 mg, 30%) as a white solid: MS (ESI) M+1=471.2.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21]4)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH2:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([O:13][C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH:12]=3)[CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cc(Oc2ccc3c(c2)CNCC3)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.22 g, 0.0051 mol) in 4M of HCl in 1,4-Dioxane (20 mL) was allowed to stir at rt for 30 min. The reaction mixture was concentrated to give N-[4-(1,2,3,4-tetrahydroisoquinolin-7-yloxy)pyridin-2-yl]cyclopropanecarboxamnide. LCMS: (FA) ES+310.3.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:6]([O:15]C)=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2].[Cl-].[NH+]1C=CC=CC=1.C1COCC1>CN(C=O)C>[C:1]([CH2:3][CH2:4][C:5]1[C:6]([OH:15])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2]
Reactant: COC(=O)c1cnc(OC)c(CCC#N)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(O)c(CCC#N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 5-(2-cyanoethyl)-6-methoxynicotinate (589 mg) in DMF (10 mL) was added pyridinium chloride (3.01 g), and the mixture was stirred at 100° C. for 4 hr. To the reaction mixture was added THF at 0° C., and the resulting precipitate was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (479 mg) as white crystals.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41]([NH2:44])[CH2:42][NH2:43]>ClCCl>[NH2:43][CH2:42][CH2:41][NH:44][C:19]([C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)=[C:10]([NH:9][CH2:8][CH:7]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=1)=[O:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: NCCN
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Yield: 86.1 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (1.1 g, 2 mmol) and 1,2-ethylenediamine (1.1 g, 18.3 mmol) was heated at 105° C. for 2.5 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.99 g, 86%).
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19]1=[O:36].C(N(CC)CC)C>C(Cl)Cl>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19]1=[O:36])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Reactant: CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCc2ccccc2)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the crude chloro(4-phenylbutyl)phosphinic acid, ethyl ester (2.6 mmole), dry methylene chloride (9.0 ml.) and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (0.72 g., 2.4 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.44 ml., 1.3 eq.) in methylene chloride (2 ml.) over 5 minutes. After 30 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (1.5 g.) is chromatographed on silica (80 g.) eluting with hexane/acetone (2:1) to give 1.0 g. of (R)-dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil after evaporation. TLC (hexane/acetone, 2:1) single spot at Rf =0.5.