Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1.[OH:20]C1C=CC(OC2C=CC(C(F)(F)F)=CN=2)=CC=1>C(O)(=O)C.Br>[OH:20][C:18]1[CH:19]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccccc1Oc1ccc(C(F)(F)F)cn1

Procedure:
2-p-Methoxyphenoxy-5-trifluoromethylpyridine (10.5 g) in glacial acetic acid (100 ml) and 48% hydrobromic acid (50 ml) were stirred and heated under reflux for 71/2 hours. The solution was then evaporated and the remaining oil treated with sodium bicarbonate solution and shaken with ether (2×300 ml). The ether extract was shaken with 2-molar sodium hydroxide solution (200 ml) and then water (150 ml). The aqueous layers were combined, acidified with 2-molar hydrochloric acid and extracted with ether (2×300 ml). The ether extract was dried and evaporated to give a brown oil identified as 2-p-hydroxyphenoxy-5-trifluoromethylpyridine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1>>[Cl:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:22](=[O:23])[NH:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1cccnc1
Reactant: CC(C)(C)c1ccc2c(c1Cl)CCN2
Product: CC(C)(C)c1ccc2c(c1Cl)CCN2C(=O)Nc1cccnc1
Yield: 58 %

Procedure:
4-Chloro-5-tert-butylindoline (D57) (0.45 g, 3.04 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to give the title compound (0.46 g, 58%) as a white crystalline solid m.p.=174°-176° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18].Cl>C1COCC1.O>[CH2:17]([O:19][C:20]([NH:11][C@H:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:8]([OH:10])=[O:9])=[O:21])[CH3:18]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
D-Phenylglycine (R) (85.2 mmol) was dissolved in anhydrous THF (260 mL) with NaHCO3 (256 mmol) in water (260 mL). Ethylchloroformate (0.235 mol) was added. After stirred at room temperature overnight, the reaction mixture was acidified to pH 3 with 1N HCl. The aqueous layer was extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give (R)-2-(ethoxycarbonylamino)-2-phenylacetic acid 41 as a white solid in 82% yield. MS (ESI, EI+) m/z=224.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].[OH-].[Na+]>C(O)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Cl
Reactant: Nc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Nc1cccc(Br)c1
Temperature: 95 °C

Procedure:
The reaction mixture of 270.0 mg of 4-chloro-3-ethoxycarbonyl-6-trifluoromethylquinoline and 150 mL of 3-bromoaniline in 4 mL ethanol was heated at 95° C. for 4 h. The reaction was then cooled in an ice-water bath and addid with 2 mL of 0.5N sodium hydroxide solution. The solid was filtered, washed with cold ethaol-water (2:1) and dried to provide 278.0 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[F:15][CH:16]1[C@H:20]([O:21][CH3:22])[CH2:19][NH:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:18]3[CH2:19][C@@H:20]([O:21][CH3:22])[CH:16]([F:15])[CH2:17]3)=[O:13])[S:10][C:3]=12
Reactant: CO[C@@H]1CNCC1F
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CO[C@@H]1CN(C(=O)c2cc3nccc(Cl)c3s2)CC1F

Procedure:
This material was prepared by the coupling of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate and (4R)-3-fluoro-4-methoxypyrrolidine in a manner as previously described for Example 1(a), step (iv). 1H NMR (CD3OD) δ 8.57 (1H, d, J=5.1 Hz), 7.94 (1H, d, J=7.2 Hz), 7.48 (1H, d, J=5.1 Hz), 5.27-5.05 (1H, m), 4.18-3.93 (4H, m), 3.78-3.75 (1H, m), 3.35 (3H, d, J=14.1 Hz). ESIMS (MH+): 315.05
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][Br:22])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(=O)OC(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(CBr)c1

Procedure:
The crude 3-methyl-benzoic acid tert-butyl ester was reacted with NBS (0.31 g, 1.726 mmol), AIBN (0.28 g, 1.726 mmol) in CCl4 (30 mL) according to the procedure for the preparation of compound 55 in example 1. After separation by chromatography eluted with CHCl3—MeOH (50:1), a mixture of two products was obtained. One of them was the product (61% pure) with MS (ESI) 272.76 (M+H+). This mixture was not further separated and directly used in the next step reaction.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23]2[CH:28]=[CH:27][C:26](Cl)=[CH:25][C:24]=2[Cl:30])=[C:17]([CH2:31][CH3:32])[N:16]=1)(=[O:3])[CH3:2].ClC1C=[C:38]([O:40]C)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[C:1]([O:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23]2[CH:28]=[CH:27][C:26]([O:40][CH3:38])=[CH:25][C:24]=2[Cl:30])=[C:17]([CH2:31][CH3:32])[N:16]=1)(=[O:3])[CH3:2]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl acetate but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a light yellow semi-solid. IR (diffuse reflectance) 2969, 2933, 1742, 1604, 1568, 1551, 1482, 1439, 1393, 1372, 1286, 1232, 1204, 1176, 1037 cm−1; OAMS supporting ions at: ESI+ 465.2; MS (EI) m/z 465 (M+); [α]25D=79 (c 0.80, methylene chloride); Anal. Calcd for C26H28ClN3O3: C, 67.02; H, 6.06; N, 9.02. Found: C, 66.99; H, 6.18; N, 8.92.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=1)[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:52]([NH2:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:18])[NH:59][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:14][N:13]=1)[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(O)c1ccc(C(=O)NCc2ccccc2)cn1
Reaction time: 8 h
Yield: 27.9 %

Procedure:
6-(2-tert-Butoxycarbonylamino-1-hydroxy-ethyl)-nicotinic acid (130 mg, 0.461 mmol), diisopropylethylamine (DIPEA) (0.426 mL, 2.44 mmol), [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (319 mg, 1.00 mmol), and benzyl amine (0.246 mL, 2.30 mmol) were dissolved into 3 mL of dry DMF and stirred overnight. LC-MS indicated formation of the coupled product. The mixture was diluted with 30 mL of EtOAc, the organic phase washed with 2×20 mL H2O and 1×20 mL of brine, dried (MgSO4) filtered and concentrated. The residue was dissolved in CH2Cll2, applied to a SiO2 column and purified (10–30% EtOAc/hexanes) to give 47.8, 27.9% of [2-(5-benzylcarbamoyl-pyridin-2-yl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]C.[CH3:16]C(CCCCCCCCC)C(O)CC>>[CH3:3][C:2]([OH:15])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:16])[CH3:1]
Reactant: CCCCCCCCCC(C)C(O)CC
Reactant: CCCCCCCCCCC(C)(O)CC
Product: CCCCCCCCCCCC(C)(C)O

Procedure:
3-methyl-3-tridecanol; 4-methyl-3-tridecanol;
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[N:18][CH:19]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[N:18][CH:19]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a mixture of (2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (288 mg) and ethanol (2.9 mL) was added 2N hydrogen chloride in ethanol (1.53 mL). After stirring at room temperature for 2 hours, resulting precipitate was collected by filtration, and washed with ethanol to give (2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide hydrochloride (138 mg).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]([CH2:30][C:31]([F:34])([F:33])[F:32])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:36]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:30][C:31]([F:34])([F:33])[F:32]
Reactant: Cc1ccccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine (example 150, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (85%). MS (ESI): m/z=271.09 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cn1ccnc1-c1cc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccnc1-c1cc2c(OC[C@@H]3CO3)cccc2o1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 4-hydroxy-2-(1-methylimidazol-2-yl)benzo(b)furan (1.10 g), (S)-glycidyl nosylate (1.33 g) and potassium carbonate (2.13 g), a crude product of the title compound was quantitatively obtained as a pale-yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-].C1C[O:42]CC1>C(OCC)(=O)C.O>[CH2:35]([O:34][C:32]([C:29]1([OH:42])[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
Under an inert atmosphere a 500 mL four necked round bottom flask (flame dried) with a mechanic stirrer was charged with 3.56 ml diisopropyl amine in 75 mL THF. At −10° C. 15.8 mL 1.6 N BuLi/hexane solution was added drop wise. The light yellow solution was stirred for 40 minutes at −10° C. and cooled then down to −75° C. 5.4 g ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate in 25 ml THF were added over 50 minutes and stirred for 3 h at −75° C. 5.5 g (2R,8S)-(+)-(camphorsulfonyl)oxaziridine in 80 mL THF were added drop wise over 1 h. The reaction was stirred for 2 h at −75° C. and then slowly warmed up over night to ambient temperature. The amber reaction solution was cooled to 5° C. and 150 mL saturated NH4Cl-solution, 50 mL water and 50 mL ethyl acetate was added and stirred for 10 minutes. The aqueous layer was separated and extracted once with 100 mL ethyl acetate. The organic layers were washed once with 200 mL brine, dried over Na2SO4, filtered off and concentrated under vacuum. The residue was purified over a silica cartridge eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 4.24 g (74%) of the title compound as light yellow viscous oil. MS (m/e): 174.2 [(M-Boc)+].
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=1)=O.[Cl:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[I:51])[NH2:47].CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:43][C:44]1[CH:45]=[C:46]([NH:47][CH2:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=2)[CH:48]=[CH:49][C:50]=1[I:51]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cn1
Reactant: Nc1ccc(I)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(I)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (4.2 g, 19.8 mmol) was added to a DCE solution (45 mL) of ethyl 3-(5-(2-formyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate, prepared as described in Example 22, (3.9 g, 9.9 mmol), 3-chloro-4-iodoaniline (3.0 g, 11.9 mmol), and AcOH (2.8 mL, 49.4 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=2[CH2:3]1.[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl>[C:18]([N:23]1[CH2:28][CH2:27][N:26]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=3[CH2:3]2)[CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1ccccc1S2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccccc32)CC1

Procedure:
19.7 g of 10-chloro-10,11-dihydro-2-methyl-dibenzo-[b,f]thiepine dissolved in 100 ml of chloroform are heated under reflux for 24 hours together with 36.5 g of 1-carbethoxy-piperazine. Then the mixture is concentrated under reduced pressure and the residue crystallised from acetone/hexane. There is obtained 1-carbethoxy-4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 96°-98° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[C:5]1[N:6]([CH3:17])[C:7](=[O:16])[C:8]2[C:13](I)=[CH:12][N:11]([CH3:15])[C:9]=2[N:10]=1)[CH2:2][CH3:3].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([CH3:31])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.C(OCC)(=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>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:13]2[C:8]3[C:7](=[O:16])[N:6]([CH3:17])[C:5]([N:4]([CH2:18][CH2:19][CH3:20])[CH2:1][CH2:2][CH3:3])=[N:10][C:9]=3[N:11]([CH3:15])[CH:12]=2)=[C:24]([CH3:31])[CH:23]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: CCCN(CCC)c1nc2c(c(I)cn2C)c(=O)n1C
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCCN(CCC)c1nc2c(c(-c3ccc(Cl)cc3C)cn2C)c(=O)n1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
A suspension of 2-(dipropylamino)-5-iodo-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (115 mg, 0.296 mmol), 4-chloro-2-methylphenylboronic acid (76 mg, 0.446 mmol), sodium carbonate (47 mg, 0.443 mmol) and tetrakis(triphenylphosphine)palladium (34 mg, 0.0294 mmol) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.75 ml) and water (0.75 ml) was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was diluted with water and ethyl acetate. The insoluble material was removed off by filtration. The filtrate was extracted with ethyl acetate (×2). The combined organic layer was washed with brine (×1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-18% hexane/ethyl acetate gradient mixture. The fractions containing the title compound were purified again by column chromatography eluting with 18% hexane/ethyl acetate using silica gel coated with amine. The desired fractions were concentrated in vacuo, and the resulting oil was crystallized from hexane and washed with pentane to give 12 mg (11%) of the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.[C:15]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][C:29](=[O:31])[CH3:30])[C:22](Cl)=[O:23])(=[O:17])[CH3:16]>ClCCl>[C:15]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][C:29](=[O:31])[CH3:30])[C:22]([NH:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:23])(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: NN1CCNC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)NN2CCNC2=O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1-Amino-2-imidazolidinone (2.61 g, 0.026 mol) was dissolved in 200 ml of dichloromethane. The solution was cooled to 0° C. and 4.1 ml of triethylamine was added, followed by 7.5 g of 3,4-bis(acetyloxy)benzoyl chloride (0.029 mol). The mixture was stirred at 0° C. for 1 hour and at room temperature for an additional hour. The precipitate was filtered off to yield 8.3 g of 1-[[3,4-bis(acetyloxy)benzoyl]amino]-2-imidazolidinone.
Reaction SMILES: [CH:1]1([CH:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O.O>[CH:1]1([CH:4]([NH:8][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COCC(N)C1CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCC(NC(=O)OCc1ccccc1)C1CC1
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H), LRMS (ESI) m/e 250.3 [(M+H)+, calcd for C14H20NO3 250.1].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]1([S:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCCCSc1ccccc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(Nc1cccc(C2CCN(CCCCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(5-chloropentyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 423.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:23])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:6][O:7][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][O:5][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Agent: N#N
Product: CCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCC)(COC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC
Temperature: 215 °C

Procedure:
A 1000 ml round bottomed flask was charged with 619.9 g (0.12 mol) PEG 150 pentaerythritol and 96.0 g (0.48 mol) lauric acid. The mass was heated to 100° C. with a N2 sparge, 1.0 g. phosphoric acid and 0.1 g. hypophosphorus acid were charged. The batch was heated to 215° C. while collecting the water of reaction, and maintained until an acid value of 12.4 was reached. The finished material was a white waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:21])[C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:18]3[CH2:19][CH2:20][C@H:16]([N:15]([CH3:21])[CH3:14])[CH2:17]3)=[O:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CN(C)[C@H]1CCNC1
Product: CN(C)[C@H]1CCN(C(=O)c2cc3ccc(Cl)cc3[nH]2)C1

Procedure:
The title compound is synthesized by condensation of 6-chloro-1H-indole-2-carboxylic acid and dimethyl-(S)-pyrrolidin-3-yl-amine analogously to the preparation of Example 2 as a colorless solid; ES-MS: M+=292.2; HPLC: AtRet=3.15 min.