Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[H-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][N:27]=[C:28]4[CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:19]=2)[CH:14]=[CH:15][C:16]=1F)#[N:10]>CN(C=O)C>[C:9]([C:11]1[CH:12]=[C:13]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][N:27]=[C:28]4[CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:19]=2)[CH:14]=[CH:15][C:16]=1[N:4]1[CH2:5][CH2:6][CH:2]([F:1])[CH2:3]1)#[N:10]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(F)c(C#N)c4)n3)cccc12
Reactant: FC1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(N5CCC(F)C5)c(C#N)c4)n3)cccc12
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A solution of 3-fluoropyrrolidine (Anichem Product List; 16.39 mg, 0.130 mmol) in DMF (2.5 ml) was cooled in an ice bath and sodium hydride (6.89 mg, 0.172 mmol) was added. The mixture was stirred for 10 mins then 1,1-dimethylethyl 3-{5-[5-(3-cyano-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1-isoquinolinyl}propanoate (D50; 58 mg, 0.130 mmol) was added. The ice bath was removed and the solution was stirred at room temperature for 3 hrs. Further sodium hydride (3.13 mg, 0.078 mmol) was added and the resulting solution was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried with magnesium sulphate and concentrated under vacuum. The residue was purified by Mass-Directed Auto-Preparative HPLC (formic acid modifier) to provide the title compound as a cream solid (14 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([C:11]4[CH:10]=[CH:9][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:13][CH:12]=4)=[O:15])[CH2:17][CH2:18]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)nc2)CC1
Yield: 4.5 %

Procedure:
Using pyrrolidin-2-one (130 mg) and (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (554 mg) described in Preparation Example 144 and by the reaction and treatment in the same manner as in Example 1, the title compound (25 mg) was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:50])[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:3]1.[OH-].[Na+]>O1CCOCC1>[O:1]=[S:2]1(=[O:50])[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:41][CH:42]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 66 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.057 mmol) and sodium hydroxide (0.567 mL, 0.567 mmol) in dioxane (1 mL) was heated up at 78° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered and the clear solution was purified by HPLC to provide the title compound as a white solid (26 mg, 63%). LCMS: m/e 691.46 (M+H)+, 2.24 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.9 Hz, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 4.06 (quin, J=7.7 Hz, 1H), 3.67-3.45 (m, 4H), 3.44-3.34 (m, 1H), 3.33-3.11 (m, 2H), 2.92-2.80 (m, 1H), 2.77-2.59 (m, 1H), 2.42-2.29 (m, 1H), 2.26-1.02 (m, 23H), 1.77 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([N:12]3[CH:20]([CH2:21][CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=4)[C:13]3=[O:24])[C:6]=2[CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>C(Cl)Cl.O1CCOCC1>[Cl:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:24])[N:12]([C:7]1[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:11]=3[CH:10]=[N:9][CH:8]=1)[CH:20]2[CH2:21][CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 2-(8-amino-5,6,7,8-tetrahydro-isoquinolin-4-yl)-5-chloro-3-ethyl-2,3-dihydro-isoindol-1-one (511.5 mg, 1.5 mmol) in DCM (15 mL) was added Et3N (3 mmol) and methanesulfonyl chloride (228 mg, 2 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 hour before it was poured into 1 N HCl in dioxane (15 mL) and washed with EtOAc (15 mL×2). After the organic layer was decanted, the aqueous layer was basified to pH>8 with satd. aq. NaHCO3 solution. After extracted with EtOAc (20 mL×2), the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (228 mg, 62%) as a mixture of four diastereomers. MS: 420.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][CH2:28][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: NCCCN
Reactant: NC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C(N)=O)cc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 7.1 %

Procedure:
A mixture of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinoline-6-carboxamide (300 mg, 0.75 mmol) and propane-1,3-diamine (306 mg, 4.14 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 120° C. under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford 23.5 mg of the desired product (yield was 7.2%). MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.70-8.69 (d, J=1.6 Hz, 1 H), 8.18-8.15 (m, 1 H), 8.10-8.08 (dd, J=1.2, 7.6 Hz, 1 H), 7.88-7.84 (t, J=6.8 Hz, 2 H), 7.73-7.72 (m, 1 H), 7.60-7.59 (m, 1 H), 6.01 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.64-3.60 (t, J=6.8 Hz, 1 H), 3.11-3.09 (m, 2 H), 2.18-2.09 (m, 2 H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH3:21])=[C:6]([CH:22]([CH3:24])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:23])[CH3:24])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-propenyl)pyridine (Example 21) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.15 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J=6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.27 (m, 1 H), 1.19 (m, 1 H), 0.76 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C21H20FNO) 329, found 330 (M+H). Anal. Calcd for C21H28FNO: C, 76.56; H, 8.57; N, 4.25. Found: C, 76.55; H, 8.48; N, 4.11. mp 49-54°C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[N:35]1([CH2:34][CH2:33][CH2:32][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OCCCN1CCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.7 %

Procedure:
A solution of 6.25 g (23.8 mmol) of triphenylphosphine, 3.30 g (21.7 mmol) of methyl 4-hydroxybenzoate, and 2.80 g (21.7 mmol) of 1-(3-hydroxypropyl)pyrrolidine in 100 mL of CH2Cl2 was treated with 3.80 mL (24.1 mmol) of diethyl azodicarboxylate in a dropwise manner. The reaction was stirred at ambient temperature for 16 h and was quenched by the addition of 20 mL of brine. The two layers were separated, and the organic layer was dried over K2CO3 and concentrated to give 6.10 g of an oily solid which was purified by flash chromatography (SiO2; 0-5% MeOH in CH2Cl2) to afford 2.46 g (9.34 mmol; 43%) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]=[O:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].N1([C:27](=[O:28])[C:26]2N(CC=O)C=NC=2N(C)C1=O)C.C(O)CO.C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[O:28][CH2:27][CH2:26][O:13]3)[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC=O
Reactant: Cn1c(=O)c2c(ncn2CC=O)n(C)c1=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC1OCCO1
Yield: 55 %

Procedure:
20.8 g 2-(3-methyl-xanthine-7-yl)-acetaldehyde (Formula IV)-prepared similarly like 7-theophyllinyl acetaldehyde Il Farmaco, Ed. Sc. 17, 73; (1962), 40.0 ethylene glycol (Formula II) 2.5 g DOWEX 50 W synthetic resin and 1,000.0 cm3 toluene are heated under stirring in a flask equipped with a water condenser and a cooler until water condensation ceases. The reaction mixture is filtered hot and the precipitate is washed with hot toluene and the filtrate is washed upon cooling with 5% sodium hydrogen carbonate and the organic layer is evaporated after drying. The residue is crystallized three times from propanol and 2-[(3-methyl-xanthine-7-yl)methyl]-1,3-dioxolane is obtained with a yield of 55%, melting point 276°-278° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41]>O1CCOCC1.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>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:46]4[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 40 mg, 0.077 mmol), K2CO3 (32 mg, 0.23 mmol) and 4-(methylsulfonyl)phenylboronic acid (23 mg, 0.12 mmol) were diluted with dioxane (1 mL)/water (300 μL) followed by the addition of Pd(PPh3)4 (8.9 mg, 0.0077 mmol). The reaction was purged with nitrogen and stirred at 55° C. for 12 hours. The reaction was cooled and concentrated. The residue was taken up in minimal DCM and purified by silica gel chromatography, eluting with hexanes:ethyl acetate (1:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 44% yield) as a clear oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CS(O[CH2:11][CH2:12][C@H:13]([NH:21]C(OC(C)(C)C)=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=O)=O>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:13]([NH2:21])[CH2:12][CH2:11][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccc(Cl)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CC[C@H](N)c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
Diethylamine (0.426 mL, 4.12 mmol) and (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (Intermediate 59) (500 mg, 1.37 mmol) were dissolved in THF (10 mL) and sealed into a microwave tube. The reaction was heated to 120° C. for 50 minutes in the microwave reactor and cooled to room temperature. The reaction mixture was concentrated and diluted with DCM (5 mL). TFA (1 mL) was added and the reaction was stirred at 20° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford (S)-1-(4-chlorophenyl)-N3,N3-diethylpropane-1,3-diamine (119 mg, 36.0%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Cl:27])=[CH:15][C:14]=1[C:28]1[O:32][N:31]=[C:30]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[C:29]=1[NH2:38])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:36]([NH:35][C:33]([C:30]1[C:29]([NH:38][C:1](=[O:3])[CH3:2])=[C:28]([C:14]2[CH:15]=[C:16]([Cl:27])[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:13]=2[O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:32][N:31]=1)=[O:34])[CH3:37]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1NC(C)=O
Reaction time: 5 h

Procedure:
To a solution of acetyl chloride (1.45 mmol) in DCM were added 5-[2,4-bis(benzyloxy)-5-chlorophenyl]-4-amino-N-ethylisoxazole-3-carboxamide (1.45 mmol, 700 mg) and TEA (1.74 mmol, 0.24 ml) dropwise. The mixture was stirred for 5 h, diluted with DCM and washed HCl 1N. The organic extract was dried and filtered. Solvents were removed under vacuo to give the crude residue that was purified by flash chromatography on silica gel.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[C@@H]1CCCN1>>[CH3:2][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]3=[CH:14][C:13]=2[CH:12]=1
Reactant: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Agent: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)cc1n2CCNC1=O
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 2, from 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 2, intermediate) and (R)-2-methylpyrrolidine (commercially available) to give the desired product as a light red solid (16%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.C1(C)C=CC(S([Cl:53])(=O)=O)=CC=1.[Cl-].[Li+]>C(#N)C.O.C(N(CC)CC)C>[Cl:53][CH2:30][CH2:29][S:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:32])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:34])[C:9]=2[CH3:33])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:35])[CH:17]=[CH:16][N:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCO)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCCl)c1=O
Temperature: 0 °C
Yield: 94.2 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide (Example 320g, 0.15 g) dissolved in acetonitrile (2 mL) was treated with triethylamine (0.048 mL) and triethylamine hydrochloride (4.16 mg) under nitrogen. The resulting solution was stirred at 0° C. before adding p-toluenesulfonyl chloride (0.055 g) over 5 min. Lithium chloride (0.064 g) was then added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (200 mL), and extracted with DCM (200 mL). The organic layer was separated, dried (MgSO4) and evaporated to afford the subtitle compound (0.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccc(F)cc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)ethanamine (20 g, 0.1 mol) and K2CO3 (28 g, 0.2 mol) in MeCN (200 mL) was added a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (18.6 g, 0.1 mol) in MeCN (20 mL). The mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give (S)-3-(1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propan-1-one (30 g, 86%), which was used for the next step without purification. 1H NMR (CDCl3): δ=1.29 (m, 3H), 2.56-2.91 (m, 2H), 3.11 (m, 2H), 3.68 (q, 1H), 7.11 (m, 2H), 7.21 (m, 2H), 7.43 (m, 2H), 7.99 (m, 2H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].N1C=CC=CC=1.[CH2:22]([C:29](O)([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([C:29]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCC(O)(Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(Cc1ccccc1)(OS(=O)(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Triflic anhydride (71 moles, 20 g) was added at -27° C to a solution of pyridine (74 mmoles, 5.9 g) in 150 ml methylene chloride with vigorous stirring. The solution was warmed to room temperature. Benzyl 2-hydroxyhexanoic acid (57 moles, 12.65 g) in 15 ml methylene chloride was added over 2 minutes. The solution was stirred for 1 hour and filtered. The liltrate was concentrated, filtered through silica gel eluted with hexane, and evaporated to yield 17.0 g of benzyl 2-(trifluoromethanesulfonylhydroxy)hexanoic acid. (MS)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=O>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Solvent: CCO
Product: O=C1NC(=O)C(c2ccc(N=Cc3ccc(Cl)c(Cl)c3)cc2)S1
Yield: 90.1 %

Procedure:
Into 20 ml of ethanol were suspended 0.50 g of 5-(4-aminophenyl)-thiazolidine-2,4-dione, and, after added 0.42 g of 3,4-dichlorobenzaldehyde thereto, the suspension was refluxed for 3 hours. After cooling by standing, the crystals deposited were collected by filtration. The crude crystals were recrystallized from ethanol to obtain 0.79 g of title compound.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Temperature: 85 °C
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.5 g, 5.9 mmol), 3-chlorophenyl boronic acid (1.83 g, 11.7 mmol), tetrakis(triphenylphosphine)-palladium (0) (0.35 g, 0.3 mmol), and sodium carbonate (2.48 g, 23.4 mmol) in a mixture of DME and water (40 mL/10 mL) was degassed to remove the oxygen and then heated at 85° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (50 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/2:1) to afford 6-(3-chlorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one as a yellowish solid (1.4 g, 82%): mp 158-159° C.; 1H-NMR (DMSO-d6) δ10.31 (s, 1H, D2O exchangeable), 7.75 (s, 1H), 7.61 (m, 3H), 7.46 (t, 1H, J=7.9 Hz), 7.39 (dd, 1H, J=7.0, 1.1 Hz), 6.96 (d, 1H, J=8.6 Hz), 1.68 (s, 6H); Anal. Calc. For C16H14CINO2 .0.1 H2O: C, 66.37, H, 4.94, N, 4.84. Found: C, 66.14, H, 4.61, N, 4.71.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.[H-].[Na+]>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)cc1

Procedure:
p-chloro-nitrobenzene and m-fluoro-phenol in tetra-hydrofuran in the presence of sodium hydride were reacted to obtain 3-(4-nitrophenoxy)-fluorobenzene which was nitrated to form 4-nitro-3-(4-nitrophenoxy)-fluorobenzene which was reacted as in Example 1 to obtain 0-[4-nitro-3-(4-nitrophenoxy)-phenyl]-hydroxylamine melting at 132° C.