Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (151 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (94 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[CH:10]2[OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(O)C(C)(C)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-3,4-dihydro-2H-naphthalen-1-one (1.42 g, 6.81 mmol) in methanol (15 mL) and dichloromethane (5 mL) is added NaBH4 (1.04 g, 27.25 mmol) in one portion. After 15 min, water is added and the organic solvents are evaporated in vacuo. The aqueous layer is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to give 7-methoxy-2,2-dimethyl-3,4-dihydro-2H-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)[N:21]=1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CC(C)(C)OC(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and 1-BOC-piperazine were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[Br:16][CH:17]([CH2:20][Br:21])[CH2:18]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:18][CH:17]([Br:16])[CH2:20][Br:21])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: OCC(Br)CBr
Product: O=C(O)c1cc(OCC(Br)CBr)c2ccccc2c1O
Temperature: 90 °C
Yield: 35 %

Procedure:
60 g (0.3 mol) of 1,4-dihydroxy-2-naphthoic acid was added to 150 ml of 2,3-dibromopropanol and, under heating at 90° C. with stirring, hydrogen chloride gas was bubbled in the mixture during a reaction period of 2 hours. The mixture was cooled to 10° to 20° C. and the crystals precipitated were collected by filteration to obtain 42.4 g (35% yield) of 1-hydroxy-4-(β,γ-dibromopropyloxy)-2-naphthoic acid.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:31]([C:33]1[C:34](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:35][C:36]([CH3:40])([CH3:39])[C:37]=1[CH3:38])#[N:32].C([O-])(=O)C.[NH4+]>C(O)C>[CH2:27]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16](=[CH:22][CH:23]=[CH:38][C:37]3[C:36]([CH3:39])([CH3:40])[O:35][C:34](=[C:41]([C:42]#[N:43])[C:44]#[N:45])[C:33]=3[C:31]#[N:32])[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=O)CC(C)(C)C2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 92.3 %

Procedure:
In 6 ml of ethanol were dissolved 173 mg (0.42 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 95 mg (0.48 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 34 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 3.5 hours. The solvent was evaporated off and the residue was purified by silica gel column chromatography to give 229 mg of a dark brown crystal (yield: 91.8%; mp: 228-230° C.)
Reaction SMILES: [CH2:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N1CCC(NCC3C4C=CC=CC=4CCC4C=CC=CC3=4)CC1)=[N:8][C:9]=2[NH:13][CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].C(N)C=C.[Cl:44]C1N=C2C(N=CN2CC=C)=C(Cl)N=1>C(O)C>[Cl:44][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[CH:12][N:4]2[CH2:1][CH:2]=[CH2:3])=[C:9]([NH:13][CH2:14][CH:15]=[CH2:16])[N:8]=1
Reactant: C=CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: C=CCNc1nc(N2CCC(NCC3c4ccccc4CCc4ccccc43)CC2)nc2c1ncn2CC=C
Solvent: CCO
Solvent: C=CCN
Product: C=CCNc1nc(Cl)nc2c1ncn2CC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-yl)methylamino]piperidino}purine ##STR14## 0.75 ml of allylamine is added to a solution of 1.15 g of 2,6-dichloro-9-allylpurine in 15 ml of ethanol and the mixture is stirred for 1 hour at room temperature and then heated at 50° C. for 30 minutes. After evaporation of the solvent, the mixture is taken up in CH2Cl2 -H2O, decanted, and the solvent is evaporated. The residue is recrystallised from ethanol. 1 g of 2-chloro-6-allylamino-9-allylpurine, melting at 110°-112° C. is obtained. 0.85 g of that compound is dissolved in 20 ml to butanol, 1.04 g of 4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]-piperidine (oil), 0.5 g of K2CO3 and 0.1 g of potassium iodide are added to the solution obtained, and the mixture is heated at reflux for 10 hours. The reaction mixture is then concentrated and the residue is taken up in CH2Cl2 -H 2 O. The mixture is decanted, the organic phase is then evaporated, and the residue is chromatographed using ethyl acetate as eluant. 0.6 g of 9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methylamino]piperidino}-purine is isolated in the form of crystals melting (cap) at 142°-144° C. The 9-allyl-2,6-dichloropurine used as starting material was prepared by reacting allyl alcohol and 2,6-dichloropurine in tetrahydrofuran according to the Mitsunobu method. The amine used as starting material was prepared by debenzylation of the corresponding piperidine melting at 78°-81° C., which was itself prepared by reductive alkylation with NaBH3CN, in methanol, of a mixture of 1-benzylpiperidone and (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamine hydrochloride melting (cap) at 275°-280° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.[CH2:16]([O:23][C:24]([NH:26][NH2:27])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCOCC>[CH2:16]([O:23][C:24]([NH:26][NH:27][C:12]([C:7]1[S:8][C:9]([CH3:11])=[C:10]2[C:6]=1[CH2:5][CH:4]1[C:2]([CH3:1])([CH3:15])[CH:3]12)=[O:14])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1sc(C(=O)NNC(=O)OCc2ccccc2)c2c1C1C(C2)C1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (2.2 g, 9.9 mmol), hydrazinecarboxylic acid benzyl ester (3.38 g, 20.4 mmol) and DIPEA (2 mL) in DCM (50 mL) is added TBTU (3.2 g, 10 mmol). The mixture is stirred at rt for 20 h. The mixture is diluted with Et2O (200 mL) and extracted with 1 M aq. NaOH (3×50 mL) and 1 M aq. HCl (2×50 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give crude N′-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carbonyl)-hydrazinecarboxylic acid benzyl ester; LC-MS: tR=1.01 min, [M+1]+=371.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[NH:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[C:21]1[NH:15][C:16](=[O:17])[NH:18][C:19]1=[O:20]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1OC
Yield: 83.3 %

Procedure:
A mixture of 3,4,5-trimethoxybenzaldehyde (2.497 g.) and hydantoin (1.276 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.17 g., 1.5 molar ratio) was added, followed by magnetic stirring and heating (90°-92°, bath temperature) for 4 hours. Usual workup gave the title compound as a yellow solid (2.950 g.), m.p. 266°-268°. Crystallization from dioxane (80% recovery) gave m.p. 268°-270°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[C:19]([C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:33][O:34][NH2:35]>CO>[CH3:33][O:34][N:35]=[C:20]([C:19]1[C:14]([O:13][C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: CON
Reactant: COC(=O)C(=O)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C(=O)OC)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of 2.7 g (7.3 mmol) of methyl [2-(1-(4-chlorophenyl)-3-pyrazolyloxy)pyridin-3-yl]glyoxylate (Example 1a.), 1.16 g of pyridine and 25 ml of methanol were admixed with 0.67 g (8.0 mmol) of O-methylhydroxylamine hydrochloride, and the mixture was stirred at room temperature for 1.5 hours. The resulting precipitate was separated off and washed with ice-cold methanol. The residue was freed from the solvent under reduced pressure. 1.2 g (42%) of the title compound were obtained as a white solid.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[BH4-].[Na+]>CCO>[N:1]1([C:6]2[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cccc(-n2cccn2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(-n2cccn2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 6-(1H-pyrazol-1-yl)picolinate (476 mg; 2.34 mmol) in anh. EtOH (10 ml) was treated with NaBH4 (443 mg; 11.71 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 16 h. After concentration to dryness under reduced pressure, the resulting residue was treated with water, and extracted with DCM. The organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (6-(1H-pyrazol-1-yl)pyridin-2-yl)methanol as a colorless oil. LC-MS (conditions A): tR=0.45 min.; [M+H]+: 176.11 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J12) (173 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (250 mg, 0.62 mmol) according to the general procedure M. Obtained as an orange foam (168 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1OCCOCCOCCOCCOC1.[H-].[Na+].[Na+].[I-].Cl[CH2:32][CH2:33][N:34]([CH2:42][CH2:43]Cl)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].[NH4+].[Cl-]>CN(C=O)C>[C:10]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:43][CH2:42][N:34]([C:35]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:41])[CH2:33][CH2:32]1)#[N:11]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 68 %

Procedure:
To a stirred solution of 2-(3,4-dichlorophenyl)acetonitrile (3.50 g, 18.8 mmol, CASRN 3218-49-3) and 15-crown-5 (0.414 g, 1.88 mmol) in DMF (75 mL) at 0° C. under nitrogen was added NaH (1.88 g, 47.0 mmol, 60% mineral oil dispersion) in 2 portions. The reaction mixture was warmed to RT and stirred 35 min then re-cooled to 0° C. NaI (2.82 g, 18.8 mmol) was added followed by a solution of freshly prepared tert-butyl bis-(2-chloroethyl)carbamate (4.56 g, 18.8 mmol) in DMF (10 mL) via syringe. The reaction mixture was warmed to RT and stirred overnight. The reaction mixture was then poured into ice cold sat'd. NH4Cl solution (250 mL) with stirring and the mixture was extracted with EtOAc (2×250 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The crude product was loaded onto a SiO2 column (Biotage 40L) and eluted with hexanes/EtOAc (6/1) to afford 4.54 g (68%) of tert-butyl 4-cyano-4-(3,4-dichlorophenyl)piperidine-1-carboxylate (356) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N:6]([CH2:10][CH3:11])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].[I-:23].[Na+]>C(#N)C>[I-:23].[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N+:6]([CH2:10][CH3:11])=[C:7]([CH3:9])[N:8]([CH2:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCCCl
Reactant: CCn1c(C)nc2cc(Cl)c(Cl)cc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC[n+]1c(C)n(CCC[Si](C)(C)C)c2cc(Cl)c(Cl)cc21

Procedure:
5,6-Dichloro-1-ethyl-2-methylbenzimidazole (22.9 g, 0.10 moles), 3-chloropropyltrimethylsilane (15.0 g, 0.10 moles), and sodium iodide (15.0 g, 0.10 moles) were suspended in acetonitrile (200 ml) and with stirring the mixture was refluxed for 17 hours. It was filtered while hot to remove NaCl and the filtrate treated with ether (300 ml). Solid which precipitated was filtered off, washed with ether and dried. Yield 11.3 g (24%) mp 213°-5°. Additional crops were obtained by concentrating the filtrates and adding more ether. The mp of each crop was lower and less exact than the previous crop but all crops contained at least some product.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[C:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([OH:27])=[O:26].S(=O)(=O)(O)O>CS(C)=O>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]#[C:32][C:31]3[CH:34]=[CH:35][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
22.6 g (0.06 mole) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate (about 85% strength) and 9 g of 4-carboxybenzaldehyde in 190 ml of dry dimethyl sulfoxide were initially taken. 21 g (0.185 mole) of potassium tert.-butylate in 5 ml of dimethyl sulfoxide were added dropwise to the stirred mixture at room temperature. Stirring was continued for 1 hour, after which the reaction mixture was poured onto 1 liter of ice water and acidified with 20% strength sulfuric acid. The resulting precipitate was filtered off under suction, washed with water and recrystallized from isopropanol to give 14 g (70%) of the title compound. Carrying out recrystallization twice more gave 6 g of pure material of melting point 263°-264° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([NH:31][C@H:32]([CH2:37][OH:38])[CH2:33][CH:34]([CH3:36])[CH3:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:35][CH:34]([CH3:36])[CH2:33][C@H:32]([NH:31][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:37][O:38][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (440 mg, 1.80 mmol) in toluene (8 mL) at room temperature, was added cesium carbonate (879 mg, 2.70 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (458 mg, 1.079 mmol) and the mixture was degassed for 5 min. The mixture was then treated with N-Boc L-Leucinol (1160 mg, 5.39 mmol) followed by palladium(II)acetate (121 mg, 0.54 mmol) and the mixture degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate and the combined filtrate was concentrated under reduced pressure to afford the crude product which was purified by combi flash (gradient of ethyl acetate and petroleum ether) to afford (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (190 mg, 0.34 mmol, 19% yield) as an off-white solid. LC/MS (ESI) m/e 426.2 [(M+H)+, calcd for C24H32N3O4426.2]; LC/MS retention time (method C): tR=2.10 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([OH:22])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.I[CH:33]([CH3:35])[CH3:34]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH:33]([CH3:35])[CH3:34])=[CH:17][CH:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:30])[F:31])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1
Reactant: Cc1nc(O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC(C)I
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nc(OC(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-ol (30.0 mg, 0.0648 mmol) in toluene (1.0 mL) was added silver carbonate (35.7 mg, 0.130 mmol) and 2-iodopropane (32.3 μL, 0.324 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The starting material wasn't consumed completely. The mixture was stirred at 50° C. for 5 hrs. After cooling the mixture was filtered through on the pad of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (29.3 mg, 0.0633 mmol, 98%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:15]([O:18][CH3:19])[O:16][CH3:17])[O:12][C:11](=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl.O>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:15]([O:16][CH3:17])[O:18][CH3:19])[O:12][CH:11]([OH:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(O)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 0.6 g of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dimethoxymethyl)-tetrahydropyran-2-one (III′) in 36 mL of dichloromethane is cooled to −78° C. after 2 mL of DIBALH (25% in toluene) are added over 10 minutes. After 1 hour of stirring at −78° C., 0.9 g of Rochelle salt in 60 mL of water are added, phases are separated and dichloromethane is distilled off. The residue is flash chromatographed (MTBE/hexane 1/1) and the solvents are distilled off to get the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH2:16][N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:23](I)[CH3:24]>CC(C)=O>[CH2:16]([N:7]1[CH2:6][CH:12]2[CH2:11][CH2:10][CH:9]([C:23]3[CH:24]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][C:13]=32)[CH2:8]1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCC2CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
4-Nitro-1-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (82 mg, 0.376 mmol) was dissolved in acetone (5 mL) and K2CO3 (104 mg, 0.752 mmol, 2.0 eq) and ethyl iodide (64.2 mg, 0.414 mmol, 32.9 μL, 1.1 eq) were added. The reaction was stirred at room temperature for 48 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-20% MeOH/CH2Cl2 as the eluting solvent to obtain 10-ethyl-4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene as a pale orange oil (68 mg, 73%). LCMS (m/e) 247 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.03 (dd, 1H, J=2.3 and 8.1 Hz), 7.94 (d, 1H, J=2.3 Hz), 7.20 (d, 1H, J=8.1 Hz), 3.17-3.08 (m, 2H), 2.95-2.86 (m, 2H), 2.43 (q, 2H, J=7.1 Hz), 2.30-2.19 (m, 4H), 1.66-1.57 (m, 2H), 0.99 (t, 3H, J=7.1 Hz).