Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: NS(=O)(=O)c1cccc(C(=O)CBr)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(S(N)(=O)=O)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 3-bromoacetylbenzensulfonamide (T. Fujikura, K. Nigata, S. Hashimoto, K. Imai, and T. Takenaka, Chem. Pharm. Bull., 1982, 30, 4092-4101).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2)(=[O:31])[CH:29]=[CH2:30]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: C=CC(=O)Cl
Product: C=CC(=O)NC1=C(C#N)C(c2cc(Br)c(OC)c(OC)c2)c2ccc(N(C)C)cc2O1

Procedure:
The title compound was prepared from 2-amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene and acryloyl chloride as a yellow solid by a procedure similar to that described for Example 80. 1H NMR (CDCl3): 6.96-6.23 (m, 7H), 5.92 (d, J=10.2, 1H), 4.73 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.96 (s, 6H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[N:2]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].[BH4-].[Na+]>ClCCCl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[N:28]=[C:27]([NH:30][CH2:11][C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=Cc1cc2ccccc2cn1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1ncc[nH]1)c1cccc2[nH]c(NCc3cc4ccccc4cn3)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.3 %

Procedure:
To a solution of 150 mg (0.95 mmol) of isoquinoline-3-carbaldehyde in dry DCE (1 mL) was added 60 mg (0.25 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B), and Ti(OiPr)4 (3 mL). The mixture was sonicated for 30 min then stirred at room temperature for 6 h. NaBH4 (0.5 g) was added, and the mixture was stirring for 12 h. The reaction was quenched by addition of methanol (2 mL). After usual workup, the residue was purified by column chromatography eluting with DCM then EtOAc/methanol (v/v=100:5) to give 7 mg (7%) of 2-[(isoquinolin-3-ylmethyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 384 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 12.58 (s, 1H), 11.8 (s, 1H), 11.6 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.22 (t, 1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.67 (m, 2H), 7.53 (t, 1H), 7.36 (d, 1H), 7.02 (t, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 4.78 (d, 2H) ppm.
Reaction SMILES: C(C1C=NC=CC=1OC1C=CC(N)=CC=1F)C.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=C[C:36]([CH2:37][NH:38][C:39]2N=CN=[C:41]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH:52][C:53]([NH:55][C:56](=[O:65])[CH2:57][C:58]4[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=4)=[O:54])=[CH:48][C:47]=3[F:66])[CH:40]=2)=[CH:35][CH:34]=1.[ClH:69].CCOCC>C(Cl)Cl.CO>[ClH:69].[CH2:35]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1[O:45][C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:53]([NH:55][C:56](=[O:65])[CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)=[O:54])=[CH:48][C:47]=1[F:66])[CH3:34]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: CCc1cnccc1Oc1ccc(N)cc1F
Agent: Cl
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCc1cnccc1Oc1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36 %

Procedure:
A solution of 4-(3-ethylpyridin-4-yloxy)-3-fluorobenzenamine (23 mg, 0.10 mmol) in CH2Cl2 (1 mL) was treated with a solution of 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.33 mL, 0.11 mmol) and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated under vacuum and the residue triturated with 1:1 isopropyl ether/EtOAc to give a yellow solid. The product was treated with absolute MeOH (1 mL) and 2 M HCl/Et2O (1 mL), stirred at room temperature for 5 min and concentrated under vacuum to give the title compound (15 mg, 36%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.57 (s, 1H), 8.41 (s, 1H), 8.26 (d, 1H, J=5.6 Hz), 7.76 (dd, 1H, J=2.0, 12.7 Hz), 7.40-7.28 (m, 4H), 7.19-7.14 (m, 3H), 6.54 (d, 1H, J=5.6 Hz), 3.73 (s, 2H), 2.72 (q, 2H, J=7.6 Hz), 1.23 (t, 3H, J=7.6 Hz); MS(ESI+): m/z 412.20 (M+H)+.
Reaction SMILES: N#N.[Si]([O:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][O:18][CH3:19])=[N:14][CH:13]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:19][O:18][CH2:17][C:15]1[S:16][C:12]([CH2:11][OH:10])=[CH:13][N:14]=1
Reactant: COCc1ncc(CO[Si](C)(C)C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1ncc(CO)s1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(methoxymethyl)thiazole (721 mg, 2.64 mmol) in THF (20 mL) was treated at 0° C. with TBAF (5.30 mL of a 1M solution in THF, 5.30 mmol) and the resulting mixture was stirred for 45 min at 0° C. The reaction mixture was diluted with EA, washed with sat. aq. NH4Cl and brine, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:9 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:9 hept-EA)=0.27. LC-MS-conditions 07: tR=0.41 min, [M+H]+=160.01.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].[NH3:13]>>[NH2:13][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1
Reactant: N
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Product: CN1C(C)(C)CC(N)CC1(C)C

Procedure:
The procedure described in Preparation 1(a) was repeated, but using as starting materials 1,2,2,6,6-pentamethyl-4-piperidone and ammonia, to give the title compound, boiling at 76°-79.5° C./5 mmHg (667 Pascals).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19].[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:46])[CH2:32][CH2:31]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:16][C:18]([N:30]1[CH2:31][CH2:32][CH:33]([N:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:46])[CH2:34][CH2:35]1)=[O:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)C(N)Cc1cc(Cl)c2[nH]ncc2c1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc(Cl)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of (±)-2-amino-3-(7-chloro-1H-indazol-5-yl)-propionic acid methyl ester (78 mg, 0.31 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with carbonyl diimidazole (50 mg, 1 equiv). The reaction was stirred for 5 min, warmed to room temperature, stirred 10 min, and treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (78 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 148 mg (94%) as a white powder. 1H-NMR (DMSO-d6, 500 MHz) δ 1.46 (m, 4H), 2.55-2.80 (m, 2H), 3.05 (dd, J=13.7, 10.7, 1H), 3.15 (m, 1H), 3.62 (s, 3H), 4.04 (d, J=13.4, 2H), 4.11 (s, 2H), 4.22-4.39 (m, 2H), 6.76 (d, J=7.9, 1H), 6.87 (dd, J=7.3, 7.3, 1H), 6.90 (d, J=8.2, 1H), 7.08 (d, J=7.6, 1H), 7.12 (dd, J=7.6, 7.6, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.15 (s, 1H), 9.18 (s, 1H), 13.48 (s, 1H). Mass spec.: 511.18 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.C12CCCCC1CCCNN=2>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: C1CCC2CCCNN=C2C1
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
4-[7-(2-Butynyl)-1,3-bis-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (0.63 g) was dissolved in a solvent mixture of tetrahydrofuran (4 ml) and methanol (2 ml), and diazabicyclo[5.4.0]undecene (0.18 ml) was added to the solution. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give 0.29 g of the title compound from the elution fraction of hexane-ethyl acetate (1:5).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][C:11]#[N:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:12][CH2:11][CH2:10][C:9]#[N:8]
Reactant: O=Cc1cccs1
Reactant: N#CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#CCCNCc1cccs1

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-propionitrile was prepared following general procedure D using thiophene-2-carboxaldehyde (477 μL, 98%, 5 mmol), 3-amino-propionitrile (373 μL, 99%, 5 mmol), 1 M acetic acid solution in DCE (6 mL), DCE (9 mL) and sodium triacetoxyborohydride (1.31 g, 97%, 6 mmol). The crude product was used without further purification. LCMS m/z: 167 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]([NH2:9])[C:3]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Reactant: C#Cc1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C#Cc2cccc(O)c2)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 500 mg (1.8 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 827 mg (7.0 mmol) 3-ethynyl-phenol, 35 mg (0.19 mmol) CuI, 129 mg (0.19 mmol) PdCl2(PPh3)2 and 4.1 mL triethylamine in 4 mL dry DMF. Yield after purification by RP-HPLC: 511 mg (100%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2ccc(Cl)c(Cl)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 11.6 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,4-dichlorophenylboronic acid (116 mg, 0.61 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 110 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (30 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 20 g, 18-32%, gradient 2.5-20% ethanol in DCM, residue dry loaded) and twice by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 48% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 50% acetonitrile) afforded (2R,3R,4S,5R)-2-{6-amino-2-(3,4-dichlorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 9 as a white solid (24.4 mg, 11%).
Reaction SMILES: [CH2:1]([N:7]([CH3:11])[C:8]([Cl:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OC([N:19]1[C@@H:24]([C@@H:25]([OH:37])[C@@H:26]([NH2:36])[CH2:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH2:23][O:22][C@@H:21]([O:38][CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:20]1)=O)(C)(C)C.N1C=CC=CC=1>ClCCl>[ClH:10].[CH:40]1([CH2:39][O:38][C@H:21]2[CH2:20][NH:19][C@@H:24]([C@@H:25]([OH:37])[C@@H:26]([NH:36][C:8](=[O:9])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:11])[CH2:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)[CH2:23][O:22]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CCCCCCN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN(C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2CCCCC2)CN1
Product: Cl
Temperature: 55 °C

Procedure:
Add hexylmethylcarbamic chloride (11 mg, 0.062 mmol) to a solution of (2R,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-cyclohexylmethoxymorpholine-4-carboxylic acid tert-butyl ester (30 mg, 0.062 mmol) and pyridine (10 μL, 0.123 mmol) in dichloromethane at 0° C. Heat to 55° C. for four days. Perform purification, isolation, trifluoroacetic acid deprotection and salt exchange according to the procedure essentially as described for (E)-2-methyl-but-2-enoic acid [(1S,2S)-2-((3R,6R)-6-cyclohexylmethoxymorpholin-3-yl)-1-(3,5-difluorobenzyl)-2-hydroxyethyl]-amide hydrochloride.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=[O:3])[CH3:2].CI.[CH3:26]C(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]2[N:9]([CH3:26])[C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[Br:19][C:18]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]([CH3:26])[C:8]=2[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[O:4][CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(OC(C)=O)c1Br)N2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(OC(C)=O)c1Br)N2C
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(OC)c1Br)N2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine (8.0 g) in N,N-dimethylformamide (80 ml) there was added at room temperature methyl iodide (16 ml) and then potassium t-butoxide (3 g). The mixture was stirred at room temperature. Over a period of 24 hours, seven further additions of methyl iodide (10 ml) and potassium t-butoxide (2 g) were made. The final reaction mixture was diluted with ethyl acetate and the solids filtered. The filtrate was washed three times with brine, dried and evaporated. Flash chromatography of the residue on a column of silica gel, eluting with a 1:9 mixture of ethyl acetate and hexane afforded 3-acetoxy-4-bromo-2,7-dimethoxy-10-methyl-10H-phenothiazine (830 mg, m.p. 189°-190° C.) and 4-bromo-10-methyl-2,3,7-trimethoxy-10H-phenothiazine (2.86 g, m.p. 135°-137° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C:12]1=[O:25])[CH3:2].[BH4-].[Na+].Cl.C(OCC)(=O)C>C(O)C.CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C:12](=[O:25])[CH2:13][CH2:14][C@@H:15]1/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCC(O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Reaction time: 7 h

Procedure:
A solution of {(Z)-4-[(R)-2-oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (0.7 g, 1.97 mmol) in 15 mL of ethanol was stirred at 0° C., and 0.082 g NaBH4 was added. The reaction was allowed to come to room temperature and stirred for 7 hours, followed by addition of a solution of hydrochloric acid in methanol (2 M, 1-2 mL) and extraction with ethyl acetate. The organic phase was dried, concentrated, purified via chromatography to yield {(Z)-4-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester, and taken directly on to the next step.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][C:7]1[C:12]2[CH:13]([CH3:23])[CH:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=1)([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CN(C=O)C>O>[CH3:1][C:2]([Si:5]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:6][C:7]1[C:12]2[CH:13]([CH3:23])[CH:14]([CH2:19][CH2:20][C:21]([OH:42])=[O:22])[C:15]([CH3:17])([CH3:18])[O:16][C:11]=2[CH:10]=[C:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=1)([CH3:4])[CH3:3]
Reactant: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCCO)C(C)(C)O2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCC(=O)O)C(C)(C)O2
Yield: 48.4 %

Procedure:
A mixture of 2.2 g (3.97 mmol) of 5-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol and 7.47 g (19.86 mmol) of pyridinium dichromate (Aldrich) in anhy. DMF (Aldrich) was stirred at RT under argon for 20 hr. The reaction was diluted with water and extracted with EtOAc. The organic phase was dried and solvent removed under reduced pressure. The residue was then purified by repeated chromatography on silica gel to give 1.1 g (48%) of 5-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid as a pale yellow foam. HR EI MS: Calc M+, 572.3322; Observed, 572.3315. Ratio of 8:1 diastereoisomers as shown by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[NH:8][C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1.IC.[CH3:20]C([O-])(C)C>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[N:8]([CH3:20])[C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1Nc2c(Cl)nc(Cl)nc2N2CCOCC12
Solvent: CI
Solvent: CS(C)=O
Product: CN1C(=O)C2COCCN2c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
2,4-Dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (500 mg, 1.818 mmol) and iodomethane (1.134 mL, 18.18 mmol) were mixed in DMSO (3 mL). 2-Methylpropan-2-olate (699 mg, 7.27 mmol) was added and the suspension was stirred overnight at room temperature. Ten more equivalents of iodomethane were added and the solution was heated at 50° C. for about 18 hours. The reaction was purified by mass-triggered preparative HPLC 20-60% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column)) to give 20 mg of 2,4-dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a tan solid. MS [M+H] Found 289.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:75]=[CH:74][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH:46]=[C:47]([C:51]([C:53]4[N:54]=[CH:55][N:56]5[CH:60]=[C:59]([Sn](CCCC)(CCCC)CCCC)[S:58][C:57]=45)=[O:52])[CH:48]=[N:49][CH:50]=3)[CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:59]3[S:58][C:57]4=[C:53]([C:51]([C:47]5[CH:48]=[N:49][CH:50]=[C:45]([CH2:44][N:41]6[CH2:42][CH2:43][N:38]([C:36]([O:35][CH2:34][C:33]7[CH:74]=[CH:75][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=7)=[O:37])[CH2:39][CH2:40]6)[CH:46]=5)=[O:52])[N:54]=[CH:55][N:56]4[CH:60]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(CN4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)c3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(CN6CCN(C(=O)OCc7ccc([N+](=O)[O-])cc7)CC6)c5)c4s3)[C@H](C)[C@H]12
Yield: 21.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methylpyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (172 mg) was prepared in the same manner as in step a) of Example 1, except that 337 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 780 mg of 7-[5-[4-(4-nitrobenzyloxycarbonyl)-piperazin-1-yl]methylpyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.