Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])([OH:8])[C:5]([OH:7])=[O:6].[O-][CH2:21]C.[Na+].[Na].CI>C(O)C.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])([OH:8])[C:5]([O:7][CH3:21])=[O:6]
Reactant: O=C(O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CCO
Solvent: O
Product: COC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Reaction time: 8 h

Procedure:
A solution of 10.0 g (0.034 mol) of 2,2′-dichlorobenzilic acid in 50 ml of ethanol was added dropwise to freshly prepared sodium ethoxide solution of 0.78 g (0.034 mol) of sodium and 100 ml of ethanol at 20° C. and stirred overnight. The solution was evaporated to dryness, the residue was dissolved in DMF and at 20° C. 9.57 g (0.0674 mol) of methyl iodide were added dropwise and the mixture was stirred for a further 72 hours. 300 ml of water were added dropwise to the resulting suspension while cooling with ice, it was extracted with diethyl ether, the organic phase was washed with water, dried over Na2SO4, and evaporated to dryness. Yield: 10.48 g (100% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:37])[C@H:10]([CH3:36])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[NH:22][C:21]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:20][C:19]=2[N:18]([CH3:35])[C:16]1=[O:17]>ClCCl>[CH3:37][N:9]([CH3:8])[C@H:10]([CH3:36])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[NH:22][C:21]([CH2:26][NH2:27])=[N:20][C:19]=2[N:18]([CH3:35])[C:16]1=[O:17]
Reactant: C[C@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)N(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CCCCn1c(=O)c2[nH]c(CN)nc2n(C)c1=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a 50% solution of trifluoroacetic acid in dichloromethane (15 ml) was added (R)-1-(5-dimethylaminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.16 g, 0.38 mmol). After stirring at room temperature for 3 hours, the solvent and excess reagent were evaporated under reduced pressure. The residue was treated with ammonia-methanol solution (2.0 M, 10 ml) and stirred for 1 hour. Concentration under reduced pressure gave the crude product which was purified by flash chromatography on silica gel eluting with ammonium hydroxide (37% in water)-methanol-ethyl acetate (2:10:1). (R)-1-(5-Dimethylaminohexyl)-8-aminomethyl-3-methylxanthine (0.062 g, 50% yield) was obtained as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl.Cl.C[Si](C)(C)CCOC[N:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([C:25]3[CH:26]=[N:27][N:28]([C:30]4([CH2:34][C:35]#[N:36])[CH2:33][NH:32][CH2:31]4)[CH:29]=3)[C:19]=2[CH:18]=[CH:17]1.Br[C:40]1[CH:53]=[CH:52][C:43]([C:44]([NH:46][C@@H:47]([CH:49]2[CH2:51][CH2:50]2)[CH3:48])=[O:45])=[CH:42][C:41]=1[F:54]>>[C:35]([CH2:34][C:30]1([N:28]2[CH:29]=[C:25]([C:24]3[C:19]4[CH:18]=[CH:17][NH:16][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:26]=[N:27]2)[CH2:31][N:32]([C:40]2[CH:53]=[CH:52][C:43]([C:44]([NH:46][C@@H:47]([CH:49]3[CH2:51][CH2:50]3)[CH3:48])=[O:45])=[CH:42][C:41]=2[F:54])[CH2:33]1)#[N:36]
Reactant: C[C@@H](NC(=O)c1ccc(Br)c(F)c1)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C1CC1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 3, Step 2-3 starting from {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride and 4-bromo-N-[(1R)-1-cyclopropylethyl]-3-fluorobenzamide (from Step 1, above). LCMS (M+H)+: m/z=485.2. 1H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 9.01 (s, 1H), 8.88 (s, 1H), 8.46 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.71 (t, J=2.5 Hz, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.17 (d, J=2.5 Hz, 1H), 6.61 (t, J=8.4 Hz, 1H), 4.53 (d, J=8.0 Hz, 2H), 4.28 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.28 (m, 1H), 1.04 (d, J=6.5 Hz, 6H), 0.82 (m, 1H), 0.30 (m, 1H), 0.20 (m, 1H), 0.06 (m, 1H), 0.01 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][O:28][NH:29][CH3:30]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([N:29]([CH3:30])[O:28][CH3:27])=[O:14]
Reactant: O=C(O)C1OCCc2c(Br)cccc21
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1OCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid (9.10 g, 35.4 mmol) and CDI (4.14 g, 42.5 mmol) in 200 mL of dry DCM was stirred at r.t. for 30 min and then O,N-dimethyl-hydroxylamine (5.99 g, 42.5 mmol) was added. The resulting mixture was stirred overnight. The solvents were removed under vacuum, and the residue was purified with silica gel column chromatography to give 5-bromo-N-methyl-N-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide. 1H-NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 4.23˜4.28 (m, 1H), 3.87˜3.92 (m, 1H), 3.71 (s, 3H), 3.19 (s, 3H), 2.71˜2.87 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Cl)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:6]2[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([NH2:1])[CH:7]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Clc1cncc(Cl)c1
Reactant: Nc1cc(O)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Oc2cncc(Cl)c2)c(F)cc1F
Temperature: 190 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-amino-2,4-difluorophenol (0.3 g, 2.07 mmol) in DMSO (2 mL) was added potassium t-butoxide (0.23 g, 2.07 mmol) at RT. After stirring for 1 h, 3,5-dichloropyridine (0.37 g, 2.5 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the mixture was heated to 190° C. for 1 h in microwave reactor. Water (30 mL) was added, and the product was extracted with EtOAc (2×35 mL) and the combined organic layers were washed with brine solution, dried (Na2SO4), concentrated in vacuo and purified by chromatography (EtOAc/hexane) to afford 5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine (0.35 g, 66% yield) as a solid. 1H NMR (400 MHz, Acetone-d6) δ 8.33-8.30 (m, 2H), 7.44 (t, J=2.4 Hz, 1H), 7.13 (t, J=10.8 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.85 (brs, 2H); MS (ESI) m/z: 257.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[C:5]([C:10]2[CH:11]=[C:12]([NH:17][C:18]3[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=3)[O:21][CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[CH:13]=[CH:14][C:15]=2[CH3:16])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[CH3:39][NH:40][CH3:41].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:39][N:40]([CH3:41])[CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[C:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([C:5]3[S:6][C:7]([S:8][CH3:9])=[C:3]([C:1]#[N:2])[C:4]=3[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CSc1sc(-c2cc(Nc3cccc(OCCCOS(C)(=O)=O)c3)ccc2C)c(-c2cccnc2)c1C#N
Reactant: CNC
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1sc(-c2cc(Nc3cccc(OCCCN(C)C)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of methanesulfonic acid 3-{3-[3-(4-cyano-5-methylsulfanyl-3-pyridin-3-yl-thiophene-2-yl)-4-methyl-phenylamino]-phenoxyl}-propyl ester (20 mg, 0.035 mmol) in DCM (1 mL) was added excess dimethylamine and excess triethylamine. The reaction was stirred at ambient temperature for 3 hours then water (2 ml) was added and the product extracted with DCM (3 mL×3). The combined organic layer were concentrated to afford the crude product as an oil. Purification by chromatography (2% MeOH—CH2Cl2) afforded the desired product (17 mg, 95%). 1H NMR (CDCl3): δ8.6(d, 1H), 8.5 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 -7.0 (m, 4H), 7.0(d, 1H), 6.5 (d, 1H), 4.1 (t, 2H), 2.9 (m, 2H), 2.7 (s, 3H), 2.6 (s, 6H), 2.1 (m, 2H), 1.6 (s, 3H).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH:28]([CH3:33])[CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.[K+].[Br-]>>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH:28]([CH3:33])[CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(c2ccnc3cc4c(cc23)OCO4)C(C)CN(C)C)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COc1cc2c(=O)n(C(C)CN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 30.4 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(N,N-dimethylamino)-1-methylethyl)-2-iodo-4,5-dimethoxybenzamide; (30.4% yield); reaction time 30 min; mp 186-187° C.; IR (KBr) 1649; 1H NMR (CDCl3); δ 1.95-1.98 (m, 9H), 2.77 (dd, 1H, J=12.0, 8.0), 3.21 (dd, 1H, J=12.0, 8.0), 4.06 (s, 3H), 4.13 (s, 3H), 4.84-4.92 (m, 1H), 6.17 (s, 2H), 7.46 (s, 1H), 7.66 (s, 1H), 7.77 (s, 1H), 7.87 (s, 1H), 9.35 (s, 1H); 13C NMR (CDCl3) δ 19.7, 45.5, 56.2, 56.3, 59.5, 63.1, 100.9, 101.9, 102.1, 107.0, 108.7, 112.4, 115.2, 120.5, 127.3, 142.6, 143.3, 147.0, 147.3, 149.9, 150.1, 154.0, 164.9; HRMS calcd for C24H25N3O5H: 436.1794; found 436.1863.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:16][N:17]([CH3:26])[C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:17]([CH3:16])[CH3:26])=[CH:19][CH:20]=2)[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccc(N(C)C)cc1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Product: CN(C)c1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloro-6-nitro-quinazoline and N1,N1,N4-trimethylbenzene-1,4-diamine by a procedure similar to example 10. 1H NMR (CDCl3): 7.71 (m, 1H), 7.51-7.56 (m, 1H), 7.07 (m, 2H), 6.99 (m, 2H), 6.71 (m, 2H), 3.59 (s, 3H), 3.01 (s, 6H).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1cc(Br)cnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ncc(Br)cc2N)cc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromopyridin-3-amine (860 mg, 3.41 mmol), 4-methoxyphenylboronic acid (519 mg, 3.41 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (120.5 mg, 0.17 mmol), and 2.0M sodium carbonate (5.1 mL, 10.2 mmol) in 1,4-dioxane (15 mL) was heated to 90° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a white solid as 5-bromo-2-(4-methoxyphenyl)pyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (1H, d, J=2.0 Hz), 7.65 (2H, m), 7.20 (1H, d, J=2.0 Hz), 7.06 (2H, m), 4.11 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)cc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (92 mg, 0.25 mmol) and 4-ethynyl-benzenesulfonamide (45 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (52 mg, 49%). MS (ISP) 423.3 [(M+H)+]; mp 230-233° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C:13]2([C:35]([F:38])([F:37])[F:36])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])=[C:20]([C:31]([F:34])([F:33])[F:32])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+]([O-])([O-])=[O:42].[NH4+].[Ce].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C:13]2([C:35]([F:36])([F:37])[F:38])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])=[C:20]([C:31]([F:32])([F:33])[F:34])[CH:19]=3)[CH:14]2[OH:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F)C1CC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: O=C(NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)cc1C(F)(F)F)C1CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-{[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl-}-4-(trifluoro-methyl)pyridin-3-yl]methyl}cyclopropanecarboxamide (0.15 g) was dissolved in acetonitrile (3 ml) and to the solution was added cerium ammonium nitrate (IV) (1 M aqueous solution, 0.51 ml) at 0° C. After stirring at 0° C. for 3 hours, an aqueous solution of sodium sulfite was added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The target compound (0.12 g) was obtained by purification with silica gel column chromatography.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]3[N:15]4[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.[H-].[Na+]>>[CH:27]1([CH2:26][N:22]2[CH2:21][CH2:20][CH2:19][N:15]3[C:16]4[CH:17]=[CH:18][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:11][C:12]=4[CH:13]=[C:14]3[C:23]2=[O:24])[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: O=C1NCCCn2c1cc1cc(OCCCN3CCCC3)ccc12
Agent: [H-]
Agent: [Na+]
Product: O=C1c2cc3cc(OCCCN4CCCC4)ccc3n2CCCN1CC1CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 17, from 9-(3-pyrrolidin-1-yl-propoxy)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 16), 1-(bromomethyl)cyclopropane and sodium hydride, to give the desired product as a white solid (29%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][C:38]#C)[CH:31]=4)[CH2:26][CH2:25]3)=[O:19])[CH:12]=2)[C:9]([C:40]([O:42][CH3:43])=[O:41])=[C:8]([CH3:44])[NH:7][C:6]=1[CH3:45])=[O:4].[CH3:46]COC(C)=O>[Pd]>[CH3:45][C:6]1[NH:7][C:8]([CH3:44])=[C:9]([C:40]([O:42][CH3:43])=[O:41])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH:37]([CH3:38])[CH3:46])[CH:31]=4)[CH2:26][CH2:25]3)=[O:19])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: C#CCOc1cccc(C2CCN(CCCNC(=O)Nc3cccc(C4C(C(=O)OC)=C(C)NC(C)=C4C(=O)OC)c3)CC2)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)NCCCN2CCC(c3cccc(OC(C)C)c3)CC2)c1
Reaction time: 3 h

Procedure:
A suspension of the product of Example 51 (316 mg, 0.519 mmol) and 81 mg of 10% Pd/C in EtOAc (65 mL) was shaken under 50 psi of H2 on a Parr Hydrogenator for 3 h. The suspension was then filtered through Celite and the filtrate concentrated in vacuo to give 325 mg of the product as a clear oil. This residue was purified by preparative HPLC (Zorbax-RX-C8 column; 45% MeCN/55% 0.1% TFA H2O; 4.2 mL/min) and the free base subsequently converted to the HCl salt to furnish the product as a colorless foam: mp 110°-130° C. (sintered); 1H NMR (CDCl3) δ10.62 (br s, 1H). 8.53 (br s, 1H), 7.34 (d, 1H, J=7.6 Hz), 7.12 (m, 3H), 7.00 (t, 1H, J=7.6 Hz), 6.86 (d, 1H, J=7.5 Hz), 6.68 (m, 4H), 4.90 (s, 1H), 3.82 (t, 2H, J=6.5 Hz), 3.54 (s, 6H), 3.45 (m, 2H), 3.20 (m, 2H), 2.75 (m, 4H), 2.62 (m, 3H), 2.25 (s, 6H), 1.92 (m, 4H), 1.72 (h, 2H, J=6.8 Hz), and 0.95 (t, 3H, J=7.3 Hz); 13C NMR (CDCl3) δ168.4, 159.4, 157.1, 148.8, 145.5, 144.4, 139.6, 129.8, 128.5, 122.0, 118.7, 118.1, 117.2, 113.6, 112.5, 102.9, 69.5, 55.2, 53.3, 51.0, 40.2, 39.1, 36.7, 30.2, 25.1, 22.6, 19.2, and 10.5. Anal. Calcd for C35H46N4O6.HCl.0.45H2O: C, 63.37; H, 7.28; N, 8.45. Found: C, 63.37; H, 7.40; N, 8.28.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:8][CH2:7]1)=[O:4].[C:9]([OH:14])(=[S:13])[CH:10](C)O.O.Cl>ClCCl>[CH:6]1([NH:5][C:3]([CH2:2][S:13][C:9](=[O:14])[CH3:10])=[O:4])[CH2:8][CH2:7]1
Reactant: CC(O)C(O)=S
Reactant: O=C(CCl)NC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)SCC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a solution of 2-chloro-N-cyclopropyl-acetamide (58.1 g, 0.435 mol) in dichloromethane (700 ml) at 0° C. is added thiolactic acid (49.65 g, 0.652 mol). The mixture is stirred at 0° C. for 5 minutes, then TEA (88.0 g, 0.870 mol) is added very slowly (exothermic reaction). The mixture is stirred at 0° C. for 2 hours, then poured over 700 ml of water with stirring. The aqueous layer is acidified to pH2 with 5 N HCl, and the layers are shaken and separated. The aqueous layer is extracted with dichloromethane (2×400 ml). The combined organic layers are washed with brine, then dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow-orange solid (74.5 g, 99%). Mass (m/z): 174.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=O)[C:19]=3[CH:20]=2)[CH:7]=1.C([N:35](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[NH4+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]([CH3:29])([CH3:30])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:25])[F:26])[CH2:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:21]([NH2:35])=[O:23])[C:19]=3[CH:20]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2c(C(=O)O)cccc2[nH]1)C(F)(F)F
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2c(C(N)=O)cccc2[nH]1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
A solution 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-4-carboxylic acid (170 mg, 0.375 mmol) in 2 mL of acetonitrile was treated with 105 mL of triethylamine and TBTU (133 mg, 0.413 mmol). After 15 minutes, 53.6 mL of ammonium hydroxide solution was added. The resulting reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (50% ethyl acetate in hexanes) gave 170 mg of the title product as an off-white solid (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8]>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)cc(F)c1
Yield: 108.6 %

Procedure:
According to the literature (Kruse et al., J. Med. Chem. (1987), 30, 486-494), a solution of 3,5-difluorocinnamic acid (9.94 g, 53.9 mmol) in THF (100 ml) was hydrogenated over 10% Pd/C (1.50 g) at 50 psi of H2 pressure for 5 h at RT. The mixture was filtered and concentrated under reduced pressure to yield the 3-(3,5-difluoro-phenyl)propionic acid (10.9 g, 100%). Oxalyl chloride (13 ml, 150 mmol) was slowly added to a solution of the acid (10.9 g, 53.9 mmol) in THF (220 ml) at 23° C., followed by the addition of a catalytic amount of DMF (1 drop). After 90 min at RT, the volatiles were removed under reduced pressure and the resulting residue was twice coevaporated with dry benzene to yield 3-(3,5-difluorophenyl)-propionyl chloride as a yellow oil (11.91 g, 100%). The acid chloride was used in the ensuing step without further purification. The acylation was carried out in analogy to the literature (Pettit et al. Synthesis (1996), 719-725). A solution of (S)-(−)-4-isopropyl-2-oxazolidinone (6.46 g, 50 mmol) in THF (150 ml) was stirred under argon and cooled to −78° C. n-BuLi (2.45 M in hexanes, 20.8 ml, 50.96 mmol) was added dropwise, followed by a solution of the previously prepared 3-(3,5-difluorophenyl)-propionyl chloride in THF (8 ml). After warming the reaction to 23° C. over 15 h, the reaction was quenched with saturated aq. NH4Cl (30 ml), followed by removal of the volatiles in vacuo. The slurry was extracted with CH2Cl2 (2×), and the combined organic layers washed with 1 M NaOH (2×) and brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by chromatography over silica gel (15→30% EtOAc/hexanes) gave the product (14.27 g, 48 mmol, 96%). 1H NMR (400 MHz, CDCl3) δ 6.73 (m, 2H), 6.59 (m, 1H), 4.37 (m, 1H), 4.17-4.25 (m, 2H), 3.24 (m, 1H), 3.16 (m, 1H), 2.93 (m, 2H), 2.30 (m, 1H), 0.86 (d, 3H, J=6.8 Hz), 0.80 (d, 3H, J=6.8 Hz); LCMS (Conditions A): tR=4.47 min: 595 (2M+H)+, 298 (M+H)+.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([C:16](=[O:18])[CH3:17])[C@H:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[N:12]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:36]([O:35][C:33]([N:12]1[C@@H:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[C@H:14]([C:16](=[O:18])[CH3:17])[CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)=O)C[C@@H](C(=O)OCc3ccccc3)N2C(=O)OC(C)(C)C)ccc1OC
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc([C@H]2[C@H](C(C)=O)C[C@@H](C(=O)O)N2C(=O)OC(C)(C)C)ccc1OC
Reaction time: 1.5 h
Yield: 91 %

Procedure:
The other isomer at position 4 may be prepared as follows: A solution of (2S,4R,5R)-4-Acetyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester benzyl ester (0.58 g) in 8 mL of methanol is treated with 0.058 g of 10% Pd/C and placed under an atmosphere of hydrogen for 90 minutes at room temperature. The catalyst is removed by filtration and the solvent removed completely to give 0.44 g of the desired compound as a viscous oil. 1H-NMR δ (d6-DMSO): 12.90 (1H, Brs, exch D2O, CO2H), 7.40 (1H, m, Ph), 6.95 (1H, m, Ph), 6.80 (1H, m. Ph), 5.17 (1H, d, PhCHN), 4.13 (1H, m NCHCO2), 4.01 (2H, m, CH2O), 3.73 (3H, s, CH3O), 3.55-3.45 (3H, m, CHCO+CH2O), 3.25 (3H, s, CH3O), 2.40-2.15 (2H, s, CH2-ring), 1.93 (2H, m, CH2), 1.85 (3H, s, Me), 1.28 (9H, s, tBu).