Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20].Br[C:29]1[C:40]([CH3:41])=[N:39][C:32]2[N:33]=[C:34]([NH:37][CH3:38])[N:35]=[CH:36][C:31]=2[CH:30]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:29]2[C:40]([CH3:41])=[N:39][C:32]3[N:33]=[C:34]([NH:37][CH3:38])[N:35]=[CH:36][C:31]=3[CH:30]=2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:20]
Reactant: CC(C)(C)CCNC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1F
Reactant: CNc1ncc2cc(Br)c(C)nc2n1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)c(C)nc2n1
Temperature: 85 °C
Yield: 47 %

Procedure:
Combine 1-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3,3-dimethylbutyl)urea (3.90 g, 10.19 mmol), 6-bromo-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine (2.58 g, 10.19 mmol) and K2CO3 (4.23 g, 30.6 mmol) in dioxane (68 mL) and H2O (17 mL) and sparge with argon. Treat with tetrakis(triphenylphosphine)palladium (0.589 g, 0.510 mmol) and heat at 85° C. overnight. Cool the mixture to RT, dilute with EtOAc, filter through diatomaceous earth, and rinse well with EtOAc. Combine filtrates and wash with water (3×) and brine (1×), dry over Na2SO4, and concentrate to dryness. Treat the residue with acetonitrile and sonicate until solids precipitate. Heat the suspension at 80° C. for 2.5 h, cool to RT and collect the solids by filtration. Re-suspend solid in MeCN, heat at 80° C. for 1 h and collect by filtration. Concentrate filtrates to dryness and purify by silica gel chromatography (EtOAc/Hex, then EtOAc/MeOH/NH4OH). Treat the purified material with MeCN, sonicate, collect solids via filtration, rinsed with MeCN and dry in vacuo. Combine the crops of solids to provide title compound (2.05 g, 47%) as a pale tan solid. MS (ESI) m/z: 429.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:23]=[CH:24][CH:25]=[C:26]4[CH:30]=[CH:29][S:28][C:27]=34)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].CCOCC>CCOC(C)=O.CO>[ClH:32].[ClH:32].[ClH:32].[S:28]1[C:27]2=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[N:23]=[CH:24][CH:25]=[C:26]2[CH:30]=[CH:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-{4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (605 mg, 1.36 mmol) was dissolved in a mixture of EtOAc (10 ml) and MeOH (1 ml) and treated with 2 N HCl in Et2O (10 ml, 20 mmol). The resulting mixture was stirred 5 h at room temperature. A white precipitate was formed that was collected by filtration and washed with EtOAc. The solid was dried over night under high vacuum to yield trans-4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride as a white solid (365 mg, 59%), MS (ISP) m/z=345.2 [(M+H)+].
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[CH2:22]([O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3ccccc3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24ClNO3+H: 386, observed: 386.
Reaction SMILES: C([Li])CCC.C([Sn]([CH2:19][O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])(CCCC)CCCC)CCC.[CH3:27][Si:28]([CH3:37])([CH3:36])[C:29]1[O:33][CH:32]=[C:31]([CH:34]=[O:35])[CH:30]=1.[C:38](Cl)(=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>CCCCCC.O1CCCC1>[C:38]([O:35][CH:34]([C:31]1[CH:30]=[C:29]([Si:28]([CH3:37])([CH3:36])[CH3:27])[O:33][CH:32]=1)[CH2:19][O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])(=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCCOC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OC(COCOCCOC)c1coc([Si](C)(C)C)c1
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.74 ml, 1.18 mmol) was added to a solution of 2-methoxyethoxy-methyl tributylstannylmethyl ether (481.6 mg, 1.18 mmol) in tetrahydrofuran (5 ml) at -78° under argon. After 10 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (198 mg, 1.18 mmol) was added, followed by lauroyl chloride (0.26 ml, 1.18 mmol) after 20 minutes. Stirring was continued at room temperature for 48 hours and the mixture was quenched with water. Extraction (ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 20% ethyl ether/petroleum ether. Fractions with Rf of about 0.27 (30% ethyl ether/petroleum ether) on evaporation afforded the title ester as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:14]3[CH2:18][NH:17][CH2:16][C@:15]3([CH2:20][OH:21])[CH3:19])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+].[OH-]>C(Cl)Cl.O>[CH2:31]([O:38][CH2:39][C:40]([N:17]1[CH2:18][C@@H:14]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH:7]=2)[C@@:15]([CH2:20][OH:21])([CH3:19])[CH2:16]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc([C@@H]2CNC[C@@]2(C)CO)cc1OCC1CC1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc([C@@H]2CN(C(=O)COCc3ccccc3)C[C@@]2(C)CO)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol (100 mg, 0.34 mmol) was dissolved in CH2Cl2 (1.7 mL), and the solution was cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed by benzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowed to warm to room temperature slowly and stirred for 18 hours. Water was added (0.25 mL) and the reaction was stirred for 1.5 hours. CH2Cl2 was added and the mixture was washed once with water, twice with iN HCl, once with water, twice with 6% NaHCO3, then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (1 mL) and cooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) was added and the hydrolysis was allowed to proceed at 0° C. for 4 hours. The reaction mixture was quenched with saturated NH4Cl, and the THF was removed by concentrated in vacuo. The residue 6% NaHCO1, dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2][NH:1][C:30](=[O:31])[O:32][CH2:33][CH3:34])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of 500 mg (1.64 mmol) of the compound from Example 101A and 321 μl (2.30 mmol) of triethylamine in 15 ml of dichloromethane was cooled to 0° C. and admixed with 189 μl (1.97 mmol) of ethyl chloroformate. The ice bath was removed and the mixture was stirred for a further 1 h. The volatile constituents were removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. The product fractions were combined and freed from the solvents on a rotary evaporator. The residue was dried in an HV. This gave 527 mg (85% of theory) of the title compound.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][C@H:3]([C:7](OCC)=[O:8])[CH2:2]1.O.[NH2:20][NH2:21]>CO.CCOC(C)=O>[NH:20]([C:7]([C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1)=[O:8])[NH2:21]
Reactant: NN
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NN)C1
Yield: 54.1 %

Procedure:
To a solution of 6.28 g (24.4 mmol) of 1-(1,1-dimethylethyl) 3-ethyl (3S)-piperidine-1,3-dicarboxylate in 25 mL of MeOH was added 7.11 mL of hydrazine monohydrate (146 mmol, 5.98 eq.). The mixture was refluxed for 2 h and concentrated. The reaction could be monitored by LC/MS on a reversed-phase column at 220 nm wavelength. The crude material was taken up in EtOAc, and washed with 2×H2O, 1× sat. aqueous NaCl, and dried over Na2SO4. Filtration and concentration afforded 3.21 g of product (54.0% yield) as a viscous oil. The product was ca. 80% pure by hplc analysis and was used as such without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>CO>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In an atmosphere of argon, 50 g (290.7 mmols) of 4-bromoaniline was dissolved in 580 ml of methanol, and the solution obtained was cooled to 0° C., and thereafter 32.6g (1.1-fold equivalent weight) of acetic anhydride was dropwise added thereto. Thereafter, the solution obtained was restored to room temperature, followed by stirring for 1 hour, and the crystals deposited were filtered off. To the residue obtained by vacuum concentration of the filtrate, 250 ml of water was added, and the crystals deposited were collected by filtration, which was then washed with water, followed by natural drying to obtain 65.5 g of N-acetyl-4-bromoaniline (yield: 100%; a white solid).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:6].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH3:6]
Reactant: CCOc1cc(C2CCNCC2)ccc1NC(=O)C(F)(F)F
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1NC(=O)C(F)(F)F
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To N-[2-(ethyloxy)-4-(4-piperidinyl)phenyl]-2,2,2-trifluoroacetamide acetate (2.2 g, 5.9 mmol) and methyl vinyl sulfone (0.74 g, 7.0 mmol) in DCM (50 mL) was added K2CO3 (1.2 g, 8.8 mmol). A few drops of MeOH were added to help solubilize the reagents. The reaction was stirred in a sealed tube three h. The reaction was filtered then purified by silica gel chromatography. The desired fractions were combined, and the solvent was removed under vacuum to provide the title compound of step F as a white solid (1.4 g, 3.3 mmol, 58%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br s, 1H), 8.18 (d, J=8.2 Hz, 1H), 6.81 (dd, J=8.2, 1.6 Hz, 1H), 6.73 (d, J=1.6 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.15 (t, J=6.6 Hz, 2H), 3.02 (s, 3H), 3.00 (d, J=11.7 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.52-2.42 (m, 1H), 2.18-2.10 (m, 2H), 1.84 (d, J=12.8 Hz, 2H), 1.73-1.60 (m, 2H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1.[C:25]([N:32]1[CH2:36][CH2:35][CH:34](O)[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]([O:27][C:25]([N:32]1[CH2:36][CH2:35][CH:34]([O:23][C:22]([C:7]2[CH:6]=[C:5]3[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]4[C:4]3=[CH:3][C:2]([Cl:1])=[C:19]3[C:14]=4[N:15]=[CH:16][CH:17]=[CH:18]3)=[CH:9][CH:8]=2)=[O:24])[CH2:33]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)C1
Yield: 48.9 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), 1-Boc-3-pyrrolidinol (0.11 g, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol) and DMF (1 ml) gave the title compound (70 mg, 47%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH2:77])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:54][C:55]([N:57]1[CH2:58][CH2:59][N:60]([C:63](=[O:78])[C@@H:64]([NH:77][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH2:61][CH2:62]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 427 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 206 mg HOBt, 258 mg EDC and 0.43 ml DIPEA. After 5 minutes 420 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid butyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (70 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 37 mg MS (ES+): m/e=800.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:26][CH2:27][C@H:28]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:29]([NH:31][C@H:32]1[CH2:38][CH2:37][S:36][C@H:35]2[CH2:39][CH2:40][CH2:41][C@@H:42]([CH2:43][OH:44])[N:34]2[C:33]1=[O:45])=[O:30])[C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][S:16][C@H:15]2[CH2:19][CH2:20]C[C@@H](CO)[N:14]2[C:13]1=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53]C([O-])(C)C.[K+].IC.[CH2:61]1[CH2:65][O:64][CH2:63][CH2:62]1>>[CH2:46]([C@@H:28]([CH2:27][CH2:26][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][S:16][C@H:15]2[CH2:19][CH2:20][CH2:62][C@@H:61]([CH2:65][O:64][CH3:63])[N:14]2[C:13]1=[O:25])=[O:10])[C:29]([NH:31][C@H:32]1[CH2:38][CH2:37][S:36][C@H:35]2[CH2:39][CH2:40][CH2:41][C@@H:42]([CH2:43][O:44][CH3:53])[N:34]2[C:33]1=[O:45])=[O:30])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: O=C(N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O)Cc1ccccc1
Agent: [K+]
Solvent: CI
Product: COC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](COC)N4C3=O)Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
To a round bottom flask at 0° C. was added (2R,5R)-2,5-dibenzyl-N1,N6-bis((4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide (24.4 mg, 0.032 mmol), THF (0.15 mL) and followed by KOtBu (1.0M in THF, 0.0715 mL, 0.071 mmol). The reaction was then warmed to rt and stirred for 15 min. Then, iodomethane (18.5 mg, 0.130 mmol) was added. The reaction was stirred at rt for 4 hr. LC/MS showed a mixture of starting material, mono-ether product and desired di-ether product. Another 71 μL of KOtBu solution was added along with another 8 μL of iodomethane. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of saturated aqueous NH4Cl. The solution was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by RP prep-HPLC (Method A). The fraction containing the product was concentrated to give (2R,5R)-2,5-dibenzyl-N1,N6-bis((4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide (3.0 mg, 0.0037 mmol, 12% yield) of a white solid. Anal. Calcd. for C42H58N4O6S2 m/z 778.5. found: 779.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.20 (4H, m), 7.18-7.11 (6H, m), 6.97-6.91 (2H, m), 5.28-5.23 (2H, m), 4.96-4.89 (2H, m), 4.71-4.65 (2H, m), 3.73-3.67 (2H, m), 3.41-3.36 (2H, m), 3.35 (6H, s), 3.23-3.15 (2H, m), 2.85-2.78 (2H, m), 2.73-2.64 (4H, m), 2.40-2.31 (2H, m), 2.09-1.95 (4H, m), 1.92-1.77 (4H, m), 1.72-1.62 (4H, m), 1.61-1.53 (4H, m), 1.51-1.44 (2H, m), 1.40-1.31 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O>[N:34]1([C:40]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C(Cl)N1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Temperature: 50 °C
Yield: 99 %

Procedure:
To 6.50 g (23.5 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 39 g of toluene and 2.62 g (25.9 mmol) of triethylamine, and the resultant mixture was stirred at 30° C. To the mixture was added dropwise 7.73 g (51.7 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 30° C. for 2 hours, and then further heated to 50° C. to effect a reaction for 2 hours. After completion of the reaction, pure water was added to the reaction mixture, and an organic phase and an aqueous phase were separated, and then the resultant organic phase was quantitatively determined by an HPLC internal standard analysis method, which showed that 9.07 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cnccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)CCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.0 g, 4.2 mmol) in acetonitrile (20 mL) was added benzyl bromide and the mixture heated at reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the resultant black oil was dissolved in MeOH (50 mL). To this solution was slowly added sodium borohydride (1.2 g, 32.0 mmol) over 10 min, then the mixture was heated at reflux for 2.5 h. After cooling to RT, the reaction mixture was concentrated in vacuo before EtOAc and an aqueous saturated solution of ammonium chloride were added. The reaction mixture was stirred at RT for 1 h. The organic layer was isolated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a cream solid (0.78 g, 59%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[N:42][N:43]2[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:45]=[C:44]3[C:40]([CH:41]=[N:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCn1ncc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCn1ncc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.390 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.199 g of 6-chloromethyl-1-(3-methoxypropyl)-1H-indazole are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=6.12.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:8])C(OCC)=O.[C:10]1([S:16][CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+].CCOCC>O>[C:10]1([S:16][CH:17]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:2]2([Cl:8])[Cl:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C=CSc1ccccc1
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1C(Sc2ccccc2)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Freshly distilled ethyl trichloroacetate (164.8 g, 0.86 mmol) is added all at once to a cold (-50° ) stirred mixture of dry methyl 3-phenylthio-2-propenoate (155.4 g, 0.8 mol), dry olefin-free pentane (600 ml) and sodium methoxide (50 g, 0.92 mol). The cold mixture is allowed to stir under nitrogen at -50° for 4 hr and is then warmed slowly to RT over a period of 24 hr. Ether and water are added, and the organic layer is separated, washed with water, dried over calcium sulfate and solvent is removed under vacuum. The residue is purified by chromatography on silica gel, giving methyl 3-phenylthio-2,2-dichlorocyclopropanecarboxylate.