Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:7]([NH:9][C@H:10]([C:15](O)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C[N:26]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH2:26])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Boc-Leu-Leu-OH (Bachem, 43.6 mmol) is dissolved in THF (250 ml) and N-methylmorpholine (43.6 mmol) is added. The mixture is cooled to −20° C. and isobutyl chloroformate (43.6 mmol) is added dropwise. The mixture is stirred for 10 min. and then a 25% aqueous solution of ammonia (52.3 mmol) is added at −20° C. The mixture is stirred for 3 hours at −20° C. to −10° C. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and evaporated. The crude product is suspended in diethylether and the solid filtered of and dried (vacuum). 14.2 g of a white powder with mp. 155-156° C., Rf=0.5 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[C:10](O)[CH:11]=[CH:12][C:13]=3O)[C:7](=[O:8])[C:5]=2[CH:6]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:10]2[C:9]3[C:7](=[O:8])[C:5]4[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=4)[C:15](=[O:16])[C:14]=3[C:13]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)[CH2:23][CH2:24]1
Reactant: NCCN1CCOCC1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCOCC3)ccc(NCCN3CCOCC3)c21

Procedure:
A 9.60 g. portion of quinizarin, 46.90 g. of N-(2-aminoethyl)morpholine and 56 ml. of water are reacted as described in Example 1 giving 9.92 g. of the desired product as a blue-black solid, mp. 158°-159° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[I:14]N1C(=O)CCC1=O.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[I:14][C:12]1[S:11][CH:10]=[C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOP(=O)(OCC)c1ccsc1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)c1csc(I)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
In 5 ml of a mixed solvent of chloroform:acetic acid=1:1, 0.1101 g (0.5 mmols) of 3-(diethoxyphosphoryl)thiophene was dissolved, to which 0.2362 g (1.05 mmols) of commercially available N-iodosuccinimide was added at room temperature. Thereafter, the reaction mixture was stirred at room temperature for 4 days. After the reaction, a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added, followed by extraction with chloroform. The organic phase was washed with a 0.2N sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane 1:1) to obtain the specified substance in the form of a yellow oil at a yield of 0.1263 g (yield: 73%). The thus obtained substance was used as it is for reaction in Example 12(9).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[O:24])[CH2:14][CH:13]2[C:30]([O:32][CH3:33])=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[O:24])[CH2:14][CH:13]2[C:30]([O:32][CH3:33])=[O:31])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)C1CN(C(=O)c2cccs2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2cccs2)c2ccccc2CN1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.0 g (8.22 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate ml of CH2Cl2 chilled to 0° C., was added slowly 16.4 ml (16.44 mmol) of 1.0 molar solution of boron tribromide in CH2Cl2. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was filtered and the solid washed with CHCl2. and H2O. The filtrate was diluted with H2O and the organic layer separated. The solvent was removed under vacuum and the solid chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 0.80 g of off white foam; Mass Spectrum (ES) 473.5 (M+H); Anal. Calc'd for C22H20N2O6S2: C, 55.9; H, 4.3; N, 5.9. Found: C, 54.5; H, 4.4; N, 5.5.
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([CH2:6][C:7]([OH:9])=O)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30])=[N:26][CH:27]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C1COCC1>[N:4]1([CH2:6][C:7]([NH:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:30])=[N:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)=[O:9])[CH2:3][CH2:2][CH2:1][CH2:5]1
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Reactant: O=C(O)CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)CN3CCCC3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A solution of 1-pyrrolidinylacetic acid (0.082 g, 0.638 mmol) in thionyl chloride (3 mL, 41.1 mmol) and DCM (3 mL) was stirred at RT for 3 h, concentrated to dryness, suspended in THF (5 mL), added to a 0° C. solution of Example C1 (0.15 g, 0.455 mmol) and DIEA (0.239 mL, 1.366 mmol) in THF (5 mL), allowed to warm to RT and stirred overnight. The mixture was treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was further purified via preparative TLC (MeOH/DCM/TEA) to afford N-((5-((2-(2-(pyrrolidin-1-yl)acetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (31 mg, 15%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.98 (s, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.20 (d, J=5.8 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.74 (dd, J=5.8, 2.4 Hz, 1H), 3.27 (s, 2H), 2.58 (s, 4H), 1.73-1.71 (m, 4H), 1.21 (s, 9H); MS (ESI) m/z: 441.2 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained by the method described in Example (113d) (125.5 mg, 0.49 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (74 mg, 0.42 mmol), WSC hydrochloride (235 mg, 1.23 mmol) and HOBT (56 mg, 0.41 mmol), to obtain 145.6 mg of the title compound as a white foamy substance (83%).
Reaction SMILES: C(OOC(C)(CCC(OOC(C)(C)C)(C)C)C)(C)(C)C.C(OOC(C1C=CC=CC=1)(C)C)(C)(C)C.C(OOC(C)(C)C)(C)(C)C.[C:46]([O:55][O:56][C:57]([C:60]1C=CC=C[CH:61]=1)([CH3:59])[CH3:58])([C:49]1C=CC=C[CH:50]=1)([CH3:48])[CH3:47].C(OC(=O)CCC(OOC(C)(C)C)(OOC(C)(C)C)C)CCC.C(OOC1(OOC(C)(C)C)CC(C)CC(C)(C)C1)(C)(C)C.C(OOOC(C)(C)C)(=O)C1C=CC=CC=1>>[C:57]([O:56][O:55][C:46]([CH2:49][CH3:50])([CH3:48])[CH3:47])([CH2:60][CH3:61])([CH3:59])[CH3:58]
Reactant: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Agent: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Agent: CC(C)(C)OOC(C)(C)c1ccccc1
Product: CCC(C)(C)OOC(C)(C)CC

Procedure:
2,5-di(tert.-butyl peroxy)-2,5-dimethyl-3-hexane; 2,5-di(tert.-butyl peroxy)-2,5-dimethyl hexane, tert.-butylcumyl peroxide; di(tert.-butyl)peroxide; dicumyl peroxide; di(tert.-butyl peroxide-iso-propyl)benzene, butyl-4,4-bis(tert.-butyl peroxy)valerate; 1,1-bis(tert.-butyl peroxy)-3,3,5-trimethyl cyclohexane; tert.-butylperoxy benzoate, diene benzoyl peroxide are e.g. suitable as a peroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.[NH4+]=[S:36].O>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19](=[S:36])[NH2:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C(N)=S)ccc23)CC1
Temperature: 100 °C

Procedure:
A microwave tube with a 5 ml capacity is charged with 45 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile, prepared in example 12, and 0.2 ml of a 20% aqueous solution of ammonium sulphide in 2 ml of methanol. The mixture is microwave-heated at 100° C. for 20 min (power set at 100 watts) and then poured into 50 ml of water and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The solid obtained is triturated in diisopropyl ether. The insolubles are filtered off under RP and dried under vacuum to give 36 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbothioamide (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.66 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.79 (m, 1H) 6.10 (d, J=8.3 Hz, 1 H) 7.33 (t, J=7.8 Hz, 2 H) 7.68 (m, 1 H) 8.18 (broad s, 1 H) 8.34 (dd, J=8.3, 1.5 Hz, 1 H) 8.40 (d, J=8.3 Hz, 1 H) 9.74 (broad s, 1 H) 10.01 (broad s, 1 H) 12.87 (broad m, 1 H) LC-MS-DAD-ELSD: 517 (+)=(M+H)(+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH:31](=O)[CH2:32][CH3:33].[BH4-].[Na+]>ClCCl.COCCOC.O>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:31][CH2:32][CH3:33])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CCCNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionaldehyde (5.1 μL, 0.10 mmol) and Ti(OPr)4 (82 μL, 0.30 mmol) were dissolved in dichloromethane (1.0 mL) and mono-glyme (1.0 mL). The mixture was allowed to stir at 25° C. for 16 hours. NaBH4 (5.7 mg, 0.15 mmol) was added and the reaction was stirred for an additional 1 h. The reaction was diluted to 5 mL with dichloromethane before water (5 mL) was added. The reaction was filtered through celite to remove the titanium salts and the layers separated. The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((propylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide (7.8 mg, 14%). ESI-MS m/z calc. 442.6, found 443.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: [NH2:1][CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1.Cl[CH2:19][C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])=O>CN(C=O)C>[CH3:25][O:24][C:23](=[O:26])[NH:22][C:20]1[N:1]=[C:2]2[CH:3]=[C:4]([C:8]3[CH:17]=[CH:16][CH:15]=[C:10]([C:11](=[O:12])[NH:13][CH3:14])[CH:9]=3)[CH:5]=[N:6][N:7]2[CH:19]=1
Reactant: CNC(=O)c1cccc(C2=CC(N)NN=C2)c1
Reactant: COC(=O)NC(=O)CCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cnn3cc(NC(=O)OC)nc3c2)c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
3-(6-Amino-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide (Intermediate A—Step E) (1 eq, 2.74 mmol, 735 mg) is added to a solution of methyl (chloroacetyl)carbamate (1.2 eq, 3.28 mmol, 498 mg) in DMF (30 ml) and the reaction mixture is stirred at 110° C. for 7.5 h. The solvent is then removed in vacuo and the product is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford [7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin -2-yl]-carbamic acid methyl ester as a green solid; [M+H]+=326
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:21]=[CH:20][C:15]([NH:16]C(=O)C)=[N:14][C:12]2=[O:13])[CH2:8][CH2:7]1)(=O)C.CO.C(N(CC)CC)C>O>[C@@H:9]1([N:11]2[CH:21]=[CH:20][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[O:10][C@H:6]([CH2:5][OH:4])[CH2:7][CH2:8]1
Reactant: CC(=O)Nc1ccn([C@H]2CC[C@@H](COC(C)=O)O2)c(=O)n1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Temperature: 10 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 22.0 L three-necked, round-bottomed flask equipped with mechanical stirrer, a thermometer and a condenser was placed in a large heating bath and charged with 1.55 kg (5.25 moles) of N-acetyl 2',3'-dideoxycytidine 5'-acetate 10.6 L of methanol, 3.1 L of triethylamine, and 1.56 L of deionized water. The heating bath was filled with hot water and the temperature was raised to 60°-65°. The flask contents were stirred at 55°-60° for 3 hr, then at ambient temperature for 12. The reaction mixture was concentrated in vacuo at 70°-80° (70 mm) on a large rotary evaporator to a volume of 2.5 L to induce crystallization. To the white semi-solid was added 1.5 L of absolute ethanol and again the mixture was concentrated in vacuo to 2.5 L volume to remove residual solvents. The white semi-solid was cooled to 10° C. for 0.5 hr and was collected by filtration and washed with 1.5 L of absolute ethanol. The damp white solid was recrystallized from 50.0 L of absolute ethanol at reflux and filtered through a sintered glass funnel to remove any particulate matter. The filtrate was concentrated in vacuo at 70°-80° (70 mm) on a rotary evaporator to a volume of 3.0 L. The semi-solid was then heated for 10 minutes without vacuum at reflux in the rotary evaporator. The mixture was cooled to 10° C. for 2 hr to effect crystallization and the white solid was collected by filtration, and washed with 2×1.0 L=2.0 L of absolute ethanol. The solid was dried in a vacuum oven at 85° C. and 1 mm overnight to yield 1.02 kg (92%) of 2',3'-dideoxycytidine as a white solid, m.p. 225°-228° C; [α]S25 +76.9° (c 0.56, H2O); [α]D25 +105.0° (c 0.50, CH3OH); lit. m.p. 215°-217°; [α]D25 +81° (c 0.635, H2O) [J. P. Horowitz, J. Chua, M. Noel, and J. T. Donatti, J. Org. Chem., 32, 817 (1967)]. The mother liquors from three batches were pooled and concentrated to a volume of 1.0 L to effect recrystallization. This solid was recrystallized from 5.0 L of absolute ethanol which was concentrated to a volume of 1.0 L to yield 2-4% additional 2',3'-dideoxycytidine. The second crop mother liquors were combined and purified by column chromatography on 70-230 mesh silica gel 60 using 65:1 methylene chloride-methanol-water as eluant. In this manner, cytosine, 5,6-dihydro-2',3'-deoxyuridine and 5,6-dihydrouracil were also isolated and characterized.
Reaction SMILES: [Cl:1][C:2]1[C:31]([O:32][CH3:33])=[C:30]([Cl:34])[CH:29]=[C:28]([Cl:35])[C:3]=1[O:4][C@@H:5]([CH3:27])[C:6]([NH:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@@H:12]([F:25])[C@@H:11]1[OH:26])=[O:7].[C:36]([NH:43][C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>>[C:39]([O:38][C:36]([NH:43][C@H:44]([C:48]([O:26][C@@H:11]1[C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([O:4][C:3]2[C:28]([Cl:35])=[CH:29][C:30]([Cl:34])=[C:31]([O:32][CH3:33])[C:2]=2[Cl:1])[CH3:27])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]1[F:25])=[O:49])[CH:45]([CH3:46])[CH3:47])=[O:37])([CH3:41])([CH3:42])[CH3:40]
Reactant: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3c(Cl)cc(Cl)c(OC)c3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3c(Cl)cc(Cl)c(OC)c3Cl)[C@@H](OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H]2F)c(=O)[nH]c1=O

Procedure:
Coupling of 1-[5-[2(S)-(2,4,6-trichloro-3-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1(A) gave 1-[3-O-[N-(tert-butoxycarbonyl)-L-valyl]-5-[2(S)-(2,4,6-trichloro-3-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white solid, m.p. 147°-149° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1>>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: ClCc1nccs1
Reactant: NCCN
Product: NCCNCc1nccs1

Procedure:
Reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 34 gives N-(2-thiazolylmethyl)ethylenediamine. Reacting this intermediate with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine. Treatment with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH3:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reactant: CNCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N-methoxyethyl-methylamine (74 mg, 0.83 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 362.3 [M+H]+; tR (HPLC conditions c): 4.04 min.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC(C3(N)CCCCC3)=O)C(=O)N2[C@H]1C(O)=O.C(NCC)C.C[O-].[Na+:31].[CH2:32]([CH:34]([CH2:38][CH2:39][CH2:40][CH3:41])[C:35]([OH:37])=[O:36])[CH3:33]>CCCCCC.C(O)C>[CH2:32]([CH:34]([CH2:38][CH2:39][CH2:40][CH3:41])[C:35]([O-:37])=[O:36])[CH3:33].[Na+:31]
Reactant: CCCCC(CC)C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)C3(N)CCCCC3)C(=O)N2[C@H]1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CCO
Solvent: CCCCCC
Product: CCCCC(CC)C(=O)[O-]

Procedure:
To 300 ml. of anhydrous ethanol is added 100 g. (0.293 mole) of anhydrous 6-(1-aminocyclohexanecarboxamido)penicillanic acid followed by 23.6 g. (0.322 mole) of diethylamine at about 20°C. with stirring. After stirring of one half hour, the solution is clarified by filtration through diatomaceous earth and the filter cake is washed with 50 ml. of a 1:1 mixture of hexane and anhydrous ethanol. The resulting solution of diethylamine 6-(1-aminocyclohexanecarboxamido)penicillanate is diluted with 500 ml. of hexane. To the slowly stirred solution of the diethylamine salt is gradually added over a thirty minute period at from about 20°-23° C., a solution of sodium 2-ethylhexanoate (prepared by the reaction of 16.6 g. (0.309 mole) of sodium methoxide with 46.5 g. (0.322 mole) of 2-ethylhexanoic acid in 200 ml. of a 1:1 mixture of anhydrous ethanol and hexane at a temperature maintained below 30°C. followed by filtration and the addition of 15 ml. of a 1:1 mixture of hexane and anhydrous ethanol to wash the filter). After addition of about 75 ml. of the solution of sodium 2-ethylhexanoate, seed material of sodium 6-(1-aminocyclohexanecarboxamido)penicillanate separately formed, is added to the solution to initiate crystallization. After complete addition of the sodium 2-ethylhexanoate solution, stirring is continued for 1/2 hour, 200 ml. of hexane is added over a 30 minute period and stirring is continued for another half hour at from about 20°-23°C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CC(O)C.C(Cl)Cl.O>[CH:25]1([O:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 20 h
Yield: 98.9 %

Procedure:
A 50 mL flask containing the 2-[(2-cyclobutoxy-3-methyl-benzoyl)-amino]-indan-2-carboxylic acid ethyl ester (1.72 g, 4.37 mmol) is charged with 1,4-dioxane (16 mL) and MeOH (16 mL). A stirring bar is added and stirring is initiated. After dissolution, water (8 mL) is added followed by the LiOH (458 mg, 10.91 mmol). After 20 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜25 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (60 mL). The layers are separated. The aqueous layer is extracted with EtOAc (30 mL). The combined organic extracts are washed with water (35 mL) and brine (35 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 1.58 g of a white solid.