Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12](Cl)(Cl)=S.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[CH:32]=[C:31]([C:33]([NH:35][NH2:36])=[O:34])[CH:30]=[CH:29][C:27]=2[N:28]=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O.CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[CH:32]=[C:31]([C:33]3[O:34][C:12]([NH:1][C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[N:36][N:35]=3)[CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(Nc4ccc5ccccc5n4)o3)cc2[nH]1
Temperature: 80 °C

Procedure:
Dissolve 2-amino-quinoline (88 mg, 0.607 mmol) in a biphasic solution of CHCl3 (15 mL) and saturated NaHCO3 (15 mL). Add thiophosgene (47 uL, 0.607 mmol) to the organic phase and stir the reaction vigorously for 3 hr. Add 2-(2,6-dichloro -phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.467 mmol) and stir overnight. Filter the reaction. Extract the aqueous phase with CHCl3 (20 mL). Concentrate the combined organics and combine with the solid. Evaporate the solvent. Add EDCI (96 mg, 0.500 mmol) and DMF (3 mL). Heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Purify the concentrate by reverse phase HPLC (35-65% ACN/H2O+5 mM NH4OH) to afford the title compound as a yellow solid: 1H NMR (400 MHz, MeOD) δ ppm 7.19 (br. s., 1 H) 7.45 (m, 1 H) 7.55-7.64 (m, 3 H) 7.69-7.75 (m, 2 H) 7.82 (d, J=7.83 Hz, 2 H) 8.05 (dd, J=8.46, 1.52 Hz, 1 H) 8.16 (d, J=9.35 Hz, 1 H) 8.32 (br. s., 1 H); MS m/z=473.0 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:28])([S:24]([CH3:27])(=[O:26])=[O:25])[C:14]([NH:16][O:17]C3CCCCO3)=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.C(Cl)Cl.O>[CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:28])([S:24]([CH3:27])(=[O:25])=[O:26])[C:14]([NH:16][OH:17])=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To a solution of (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (100 mg, 0.242 mmol) in dioxane (2 mL), DCM (2 mL) and water (500 uL) was added a 4.0M sol of HCl in dioxane (0.36 mL, 1.45 mmol). The reaction mixture was stirred at RT for 30 minutes. The solvent was removed and the crude mixture was purified by HPLC (Column: Phenomenex Luna (2) C18 150×3.0 mm 5μ; flow rate 0.75 mL/min; Gradient: 5-100% MeOH/Water containing 0.1% TFA) to give (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (4 mg, 5% yield). LC-MS M+H+330.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@@H:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][N:13]=[N+]=[N-])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.C1(S)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(CCCN=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(CCCN)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N-(tert-butoxycarbonyl)-4-(3-azidopropyl)-L-proline ethyl ester (1.17 g, 3.58 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and dry tin chloride (1.01 g, 1.5 eq.), thiophenol (2.21 mL, 6 eq.) and triethylamine (2.24 mL, 4.5 eq.) were added. The reaction mixture was stirred at 25° C. for Ihour, poured into ethyl acetate, washed with 1 N HCl, 1 N NaOH, brine, dried (Na2SO4) and concentrated. The residue (0.96 g, 90%) was used crude in the next step: 1H NMR (400 MHz, CDCl3, 7:3 mixture of diastereomers) δ 1.29 (m, 3H), 1.40-1.56 (m, 9H), 1.84 (m, 1H), 2.10 (m, 1H), 2.39 (m, 1H), 2.42 (m, 1H), 2.72 (m, 2H), 2.99 (m, 2H), 3.76 (m, 2H) 4.18-4.38 (m, 4H).
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([NH:12][CH:13]([C:31]([OH:33])=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[OH:30])(=[O:21])=[O:20])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>>[C:5]([O:9][C:10]([NH:12][CH:13]([C:31]([OH:33])=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[C:23]([OH:30])=[C:24]([NH:29][C:43]([NH:42][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([Cl:41])[C:35]=2[Cl:34])=[O:44])[CH:25]=[CH:26][C:27]=1[Cl:28])(=[O:20])=[O:21])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O)C(=O)O
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O)C(=O)O
Yield: 30.2 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]-3-amino-6-chloro-2-hydroxybenzenesulfonamide (233 mg, 0.518 mmol) and 2,3-dichlorophenylisocyanate (98 mg, 0.518 mmol) were coupled to form the desired urea (100 mg, 30%). LC-MS (m/z) 641.2 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:21]3[N:25](COCC[Si](C)(C)C)[C:24]4[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=4[N:22]=3)[C:9](=[O:20])[N:10](COCC[Si](C)(C)C)[N:11]=2)=[CH:2]1>ClCCl.FC(F)(F)C(O)=O.C(S)(S)C>[NH:25]1[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=[C:21]1[C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccsc2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: CC(S)S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2ccsc2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30 mg of 6-thiophen-3-yl-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanyl -ethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one is dissolved in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml), 18 μl of ethanedithiol are added, and the resulting solution is stirred at room temperature for 18 hours. After the solvent has been distilled off, the crude product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(-c3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (example 283, Step 2) and biphenyl-3-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid. (Example 285, Step 1), to produce a white solid. MS (ES) for C24H24O5 [M−H]−: 391.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:24])[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Ni]>[Cl:24][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH2:23][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15](=[O:25])[NH:16]2
Reactant: [H][H]
Reactant: O=C1Nc2cccc(Cl)c2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Ni]
Product: O=C1Nc2cccc(Cl)c2CN1C1CCNCC1

Procedure:
100 mg (3-(1-benzyl-piperidin-4-yl)-5-chloro-3,4-dihydro-1H-quinazolin-2-one and 15 mg Raney nickel were stirred for 12 h at RT in a hydrogen atmosphere (30 psi). The reaction was filtered and the filtrate was evaporated to give 67 mg of the desired product. (M+H)+: 266
Reaction SMILES: [C:1]12([C:8]3[CH:13]=[C:12](Cl)[N:11]=[N:10][C:9]=3[Cl:15])[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[C:1]12([C:8]3[C:9]([Cl:15])=[N:10][N:11]4[C:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:24][N:25]=[C:12]4[CH:13]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1cc(C23CCC(CC2)C3)c(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2

Procedure:
A mixture of 4-(bicyclo[2.2.1]hept-1-yl)-3,6-dichloropyridazine (1 g, 4.1 mM), benzoic hydrazide (0.84 g, 6.2 mM) and triethylamine hydrochloride (0.85 g, 6.2 mM) in p-xylene (80 ml) was heated at reflux for 18 hours, after which time more benzoic hydrazide (0.28 g, 2 mM) and triethylamine hydrochloride (0.28 g, 2 mM) were added and the reaction heated at reflux for a further 3 hours. The mixture was allowed to cool, then placed directly onto silica gel for purification by column chromatography using ethyl acetate/hexane mixtures as the eluent. This yielded the title compound (0.38 g, lower Rf of the two isomeric products). 1H NMR (250 MHz, CDCl3) δ1.55-2.06 (8H, m), 2.22 (2H, m), 2.44 (1H, m), 7.25 (3H, m), 8.13 (1H, s), 8.45 (2H, m); MS (ES+) m/e 244 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]#[C:10][Si](C)(C)C)=[C:5]([C:7]#[N:8])[N:6]=1.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[CH3:15][O:16][CH:10]([O:19][CH3:18])[CH2:9][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]#[N:8]
Reactant: CO
Reactant: C[O-]
Reactant: Cc1nc(C#N)c(C#C[Si](C)(C)C)s1
Agent: [Na+]
Product: COC(Cc1sc(C)nc1C#N)OC
Reaction time: 2 h

Procedure:
2-Methyl-5-trimethylsilanylethynyl-thiazole-4-carbonitrile (4.56 g, 20.7 mmol) was dissolved in 45 ml methanol and sodium methoxide (5.4N in methanol, 11.5 ml, 62 mmol) was added. The reaction mixture was stirred for 2 hrs at reflux and extracted two times with ethyl acetate and saturated NaHCO3-solution. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (4.5 g, >100%) was used without any further purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1([F:18])[CH2:17][NH:16][CH2:15]1.[C:19]12([C:29](Cl)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[O:20]1)[CH2:26]2.C(N(CC)CC)C>C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:29]([C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]4)[O:20]2)[CH2:26]3)=[O:30])=[C:3]([C:4]([N:16]2[CH2:17][C:14]([F:18])([F:13])[CH2:15]2)=[O:6])[CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: FC1(F)CNC1
Reactant: O=C(Cl)C12CC3CC(CC(C3)O1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1cc(Cl)ccc1NC(=O)C12CC3CC(CC(C3)O1)C2)N1CC(F)(F)C1

Procedure:
2-Amino-5-chlorobenzoic acid (0.25 g) and 3,3-difluoro-azetidine hydrochloride (0.24 g) were reacted according to the method of Example 332C. The resultant intermediate (0.16 g) was then reacted with 2-oxaadamantane 1-carbonylchloride (1.25 equiv) (prepared from 2-oxaadamantane 1-carboxylic acid and thionyl chloride as in Example 12) and triethylamine (2 equiv) in acetonitrile (10 mL). Evaporation of solvents and flash chromotography over silica gel (20% ethyl acetate/hexane) provided 190 mg of the title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ 1.66-2.03 (m, 10H), 2.19 (br s, 2H), 4.36-4.81 (br, 4H), 7.54 (dd, 1H), 7.59 (d, 1H), 8.18 (d, 1H), 10.52 (s, 1H); MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[N:3]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1>>[ClH:1].[ClH:1].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[N:3]=2)[CH2:33][CH2:32]1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cc(Cl)cc(Cl)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3cc(Cl)cc(Cl)c3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
360 mg of the product obtained in Stage 1 above and 450 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 6 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:21])[CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[CH2:26][S:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:22])[CH2:10][C:11](=[O:21])[NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]2=3)=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: COc1ccc2c(c1)NC(=O)CC(=O)N2c1ccc(N)cc1
Product: COc1ccc2c(c1)NC(=O)CC(=O)N2c1ccc(NS(=O)(=O)Cc2ccccc2Cl)cc1
Yield: 21.5 %

Procedure:
By using 1-(4-aminophenyl)-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (65 mg, 0.22 mmol), and 2-chlorobenzylsulfonyl chloride (74 μL, 0.33 mmol), the title compound (23 mg, yield 13%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:8][C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:10].[Cl-]>>[C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH2:4][CH2:7][CH2:8][CH2:9][CH2:16][CH2:17][CH2:17][CH2:16][CH2:9][CH2:8][CH3:7].[C:17]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][C:9]([CH2:8][C:7]([O:23][CH2:24][CH3:25])=[O:22])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:10]
Reactant: CCCC(=O)O
Agent: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Agent: [Cl-]
Product: CCCCCCCCCCCCCC(=O)O

Procedure:
The same procedure was used as for preparation of triethyl citrate butyrate but using myristryl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=[CH:23][N:22]=2)[CH2:11]1)(C(C)(C)C)(C)C.F.N1C=CC=CC=1>C1COCC1.N1C=CC=CC=1>[CH3:18][C:16]1([CH3:19])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]3[CH:26]=[C:25]([C:27]#[C:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]=[CH:23][N:22]=3)[CH2:11][C@H:10]([CH2:9][OH:8])[C@H:14]2[O:15]1
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(C#Cc4ccccc4)ncn3)[C@@H]2O1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(C#Cc4ccccc4)ncn3)[C@@H]2O1
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
To a solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-(phenylethynyl)pyrimidin-4-amine (0.275 g, 0.573 mmol) in THF (2 mL) and pyridine (2 mL) in a teflon vial was added pyridine hydrofluoride (1.3 mL, 0.014 mol) dropwise. The reaction was stirred for 1.5 h then quenched using a saturated aqueous Na2CO3 solution (15 mL) and EtOAc. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 to 5% MeOH/EtOAc) to afford the title compound as a yellow solid (0.172 g, 82%). LC/MS: Rt=1.29 min, ES+ 366 (FA standard).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:16][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=3)[CH2:14]2)=[O:12])=CC=1)([O-])=O.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>>[N:27]1[CH:28]=[CH:29][N:30]=[CH:31][C:26]=1[NH:25][C:11]([N:13]1[CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:16]1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(Br)cn2)C1
Reactant: Nc1cnccn1
Product: O=C(Nc1cnccn1)N1CC(Oc2ccc(Br)cn2)C1
Yield: 56.4 %

Procedure:
This compound was prepared by the method outlined for example 5 step 4. Thus 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (905 mg, 2.30 mmol) was reacted with 2-aminopyrazine (243 mg, 2.53 mmol) to afford the title compound (454 mg, 56%) as off white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:18])=[N:9][N:10]([CH:15]([CH3:17])[CH3:16])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.Cl>CCO.O.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:18])=[N:9][N:10]([CH:15]([CH3:16])[CH3:17])[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Temperature: 80 °C
Yield: 99.2 %

Procedure:
7-Nitro-2-isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.015 mol) was dissolved in a 5:1 mixture of EtOH and water (150 ml). To this solution was added iron powder (2.14 g, 0.039 mol) and concentrated HCl (1 ml), the mixture was heated to 80° C. for 3 hours. After this time, the reaction mixture was cooled to RT and filtered through a pad of celite, the celite was washed with EtOH (100 ml), and the solution was concentrated under vacuum to give the title compound (4.2 g, 98% yield) as a white solid. δH (400 MHz, DMSO), 7.56 (1H, d), 7.28 (1H, s), 7.13 (1 H, d), 6.47 (2H, s), 5.24-5.09 (1H, m), 1.23 (6H, d) Tr=1.34 min m/z (ES+) (M+H)+ 282, 284
Reaction SMILES: N12CCCN=C1CCCCC2.[CH:12]([C:14]([CH2:16]C)=[O:15])=[CH2:13].[CH2:18]([O:20][C:21](=[O:34])[CH2:22][NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:19]>C1COCC1.CCOCC>[CH2:18]([O:20][C:21]([CH:22]1[C:14]([OH:15])([CH3:16])[CH2:12][CH2:13][N:23]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)(=[O:25])=[O:26])=[O:34])[CH3:19]
Reactant: C=CC(=O)CC
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1N(S(=O)(=O)c2ccc(C)cc2)CCC1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (7 mL, 47.08 mmol) was added to a stirred solution of ethyl vinyl ketone (1.75 mL, 21.4 mmol) and ethyl N-p-toluenesulfonylglycinate 81 (5.5 g, 21.4 mL) in THF (50 mL). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with ether, washed with 5% aq. HCl, 5% sodium bicarbonate solution and water. The combined organics were dried with Na2SO4, filtered, evaporated under reduced pressure to give crude 82 (5.3 g, 76%) as a yellow oil (diastereoisomers mixture). 1H-NMR (400 MHz, CDCl3): δ 1.29 (m, 6H), 1.75 (m, 1H), 2.09 (m, 1H), 2.43 (s, 3H), 3.40 (m, 1H), 3.56 (m, 1H), 4.04 (s, 1H), 4.20 (m, 2H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 14.12, 15.28, 23.04, 25.60, 26.27, 38.20, 38.86, 46.26, 46.46, 61.49, 61.65, 69.10, 71.69, 127.51, 129.70, 134.83, 134.91, 143.58, 143.84, 170.03, 170.45 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 14.12, 15.28, 23.04, 25.60, 26.27; CH2 carbons: 38.20, 38.86, 46.26, 46.46, 61.49, 61.65; CH carbons: 69.10, 71.69, 127.51, 129.70 ppm.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[O:8]=[C:9]([C:30]1[CH:31]=[C:32]2[C:37]3=[C:38]([CH2:40][CH2:41][N:36]3[C:35](=[O:42])[CH2:34][CH2:33]2)[CH:39]=1)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C(=O)OC(C)(C)C>C(O)C>[ClH:7].[C:24]1([CH2:23][CH2:22][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:30]2[CH:31]=[C:32]3[C:37]4=[C:38]([CH2:40][CH2:41][N:36]4[C:35](=[O:42])[CH2:34][CH2:33]3)[CH:39]=2)=[O:8])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)c1cc2c3c(c1)CCN3C(=O)CC2)CCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCCCNCCc1ccccc1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 4N hydrogen chloride-ethyl acetate solution was added to a solution of tert-butyl 5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(2-phenylethyl)carbamate (3.00 g) obtained in Reference Example 19 in ethanol (5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (1.98 g) having a melting point of 166 to 168° C.
Reaction SMILES: [C:1](=[O:9])([O:7][CH3:8])[O:2][CH2:3][CH:4]([F:6])[F:5].C(Cl)(=O)O[CH2:12][CH2:13]C.C(Cl)(=O)OC>>[C:1](=[O:9])([O:7][CH2:8][CH2:12][CH3:13])[O:2][CH2:3][CH:4]([F:6])[F:5]
Reactant: COC(=O)OCC(F)F
Reactant: CCCOC(=O)Cl
Agent: COC(=O)Cl
Product: CCCOC(=O)OCC(F)F

Procedure:
2,2-Difluoroethyl n-propyl carbonate was prepared as in [Synthesis of 2,2-Difluoroethyl Methyl Carbonate] of Example IV-1, except that propyl chlorocarbonate (7.4 g, 0.073 mol) was substituted for methyl chlorocarbonate (6.9 g, 0.073 mol).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1)[CH3:2].[ClH:27].CO>>[ClH:27].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: CCc1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 82 (93.7 mg) and 10% hydrogen chloride/methanol solution (2 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (63.2 mg) as light yellow powdery solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[C:9]([Cl:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>>[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)=[C:9]([Cl:18])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:28][CH2:29]1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Reactant: Fc1ccc(-c2c(Cl)sc3ncnc(Cl)c23)cc1
Product: Fc1ccc(-c2c(Cl)sc3ncnc(NC4CCN(Cc5cc(F)cc(F)c5)CC4)c23)cc1

Procedure:
The title compound was prepared (140 mg, 49%) from 4,6-dichloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (175 mg, 0.59 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (170 mg, 0.7 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 6.85 (m, 2H), 6.65 (m, 1H), 4.65 (m, 1H), 4.05 (bs, 1H), 3.40 (s, 2H), 2.40 (m, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.15 (m, 1H). MS (ESI) m/z: Calculated: 488.1; Observed: 489.2 (M++1).