Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I-:17].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:11][C:12](=[O:15])[CH2:13][I:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)C(NC(=O)CCl)C(=O)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(NC(=O)CI)C(=O)OCC

Procedure:
A solution of 5.02 g (0.02 mole) of (2-chloroacetamido)-malonic acid diethyl ester [see Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-110 (1954)] and 4.50 g (0.03 mole) of sodium iodide in 100 ml of acetone is refluxed for 30 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed once with diluted aqueous sodium bisulphite solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is recrystallized from methylene chloride/hexane. After filtration with suction and drying in vacuo, there is obtained (2-iodoacetamido)-malonic acid diethyl ester, m.p. 95°-97°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[P:10](OCC)([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11]>[Ni](Cl)Cl.O>[CH2:13]([O:12][P:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9])([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: CCOP(=O)(OCC)OCC
Reactant: Cc1cccc(Br)c1C
Agent: Cl[Ni]Cl
Solvent: O
Product: CCOP(=O)(OCC)c1cccc(C)c1C
Yield: 61.2 %

Procedure:
A mixture solution of 25.0 g (0.135 mol) of 3-bromo-o-xylene and 2.0 g (0.015 mol) of anhydrous nickel chloride was heated to 150° to 160° C., to which 26.9 g (0.162 mol) of triethyl phosphate was added for 1 to 2 hours. After the completion of the addition, it was mixed at that temperature and then cooled. To the cooled solution, 30 ml of water was added and mixed for another 30 minutes. It was then extracted three time with 100 ml of diethyl ether. The extracted solution was rinsed three times with a 5% sodium hydrogencarbonate solution and dried with anhydrous sodium sulfate. The ether solution was condensed and subjected to column chromatography to obtain 20 g of transparent liquid which had a chart (FIG. 2) of NMR spectrum in CDCl3 to find the following chemical structure; ##STR14##
Reaction SMILES: [CH:1]1([C:8](=O)[CH:9]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[C:10]([O:12]CC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:1]1([C:8]2[N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[N:25]=[C:10]([OH:12])[C:9]=2[C:15]2[C:16]([F:23])=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Reactant: Nc1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2nccn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
A mixture of ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate (342 mg, 1.0 mmol), 2-aminoimidazole (Helv. Acta. Chim. 76, 2066 (1993))(83 mg, 1.0 mmol), and 0.5 mL of tributylamine is stirred under nitrogen atmosphere at 160° C. for 1.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acide (×2) and saturated sodium chloride, dried over magnesium sulfate, and concentrated to give crude 5-cycloheptyl-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-7-ol as a dark oil (294 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH2:22]>CO>[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:23][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=2[O:12][CH3:13])[N:22]=1
Reactant: COc1ccc(Cl)cc1C(=O)CBr
Reactant: COC(=O)CCCCC(N)=O
Solvent: CO
Product: COC(=O)CCCCc1nc(-c2cc(Cl)ccc2OC)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 2-bromo-1-(5-chloro-2-methoxy-phenyl)-ethanone (12.0 g, 46 mmol) with 5-carbamoyl-pentanoic acid methyl ester (12.7 g, 79.9 mmol) and heat the neat mixture in a sealed vessel at 120-140° C. for about 6 h. Cool the mixture and add methanol and allow the mixture to stir overnight at room temperature. Concentrate the mixture and partition the residue between aq NaHCO3 and EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (CHCl3) allows for recovery of 5-[4-(5-chloro-2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (5.5 g, 37%). MS (ES): (M+1)+ 324.1, 326.1 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.N1CCCC1C(O)=O.[CH2:28]([S:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2)[CH3:29]>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:30][CH2:28][CH3:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=2)[CH:15]2[C:16](=[O:17])[O:18][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CCSCc1cccc2cc[nH]c12
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CCSCc1cccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (7.14 mmol) of 4-chlorobenzaldehyde, 1.03 g (7.14 mmol) of Meldrum's acid and 39.1 mg (0.34 mmol) of D,L-proline were added to a solution of 1.30 g (6.80 mmol) of the compound from Example 10A in 57 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the crude product was stirred in diethyl ether and filtered, and the precipitate was dried under high vacuum to result in 1.38 g (44% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[C:54]=1[C:55](O)=[O:56].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:55]([C:54]1[C:58]([CH3:62])=[CH:59][CH:60]=[CH:61][C:53]=1[Cl:52])=[O:56]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(C)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a suspension of 4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.758 mmol, 300 mg), HBTU (0.84 mmol, 318 mg) and 2-chloro-6-methylbenzoic acid (0.84 mmol, 142 mg) in DMF (2 mL) was added diisopropylethylamine (1.9 mmol, 0.33 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 48 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 380 mg (98% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H30ClN3O5 (M+Na) 535.1026, found 535.1024.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1N
Yield: 63 %

Procedure:
The title compound is prepared from 3-amino-4-methyl-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 63% of theory; LC (method 4): tR=1.81 min; Mass spectrum (ESI+): m/z=307 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33]Cl>>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][N:19]1[CH2:18][CH2:17][CH:16]([C:9]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:8]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Product: COC(=O)c1ccccc1OCCN1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1, part H, starting with 0.28 g (1 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.26 g (1.2 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. After standard work-up and purification, 0.16 g (35% of yield) of the expected product were obtained.
Reaction SMILES: C([C@@H]1COC(=O)N1C(=O)[C@@H:15]([CH3:29])[C@@H:16]([OH:28])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[I:27])C1C=CC=CC=1.[OH-:31].[Li+].OO.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:54]([CH2:57]C)CC)C>>[I:27][C:18]1[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:17]=1[C@@H:16]1[O:28][C:57](=[O:31])[NH:54][C@H:15]1[CH3:29]
Reactant: [OH-]
Reactant: CCN(CC)CC
Reactant: C[C@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)c1cc(C(F)(F)F)ccc1I
Agent: OO
Agent: [Li+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)ccc1I

Procedure:
Following the procedure described in EXAMPLE 95, Step B, 0.214 g of (4R)-4-benzyl-3-{(2S,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-one, 0.034 g of lithium hydroxide, 0.16 mL of a 30% aqueous solution of hydrogen peroxide, 0.1 mL of diphenylphosphoryl azide, and 0.072 mL of triethylamine provide the title compound. Mass spectrum (ESI) 372.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.02 (d, J=8 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s, 1H), 5.39 (d, J=4 Hz, 1H), 3.76 (dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6 Hz, 3H). Analytical HPLC on Chiralpak AD 4.6×250 mm, eluting with 4% ethanol in heptane at 0.75 mL/min (tR=21.56 min for R,R; tR=18.00 min for S,S) showed 99% e.e.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.[F:26][CH2:27][CH2:28][NH2:29]>>[F:26][CH2:27][CH2:28][NH:29][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:17][C:18]([CH3:23])([CH3:24])[C:19]([CH3:22])([CH3:21])[O:20]2)=[CH:12][CH:11]=1)=[O:7]
Reactant: NCCF
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C

Procedure:
Method as described for intermediate 13 using phenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 17) and 2-fluoroethylamine to afford a pink wax (3.8 g) used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:13]([F:16])([F:15])[F:14])[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)CO1.C[Si]([C:21]#[N:22])(C)C.[C:23](=[O:26])(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[F:16][C:13]([F:14])([F:15])[C:2]([NH:6][CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:23][OH:26])([CH3:1])[C:21]#[N:22]
Reactant: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Reactant: O=C([O-])O
Reactant: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C#N)(NC(CO)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Under argon, 52.8 g (228.3 mmol) of 2-methyl-4-phenyl-2-(trifluoromethyl)-1,3-oxazolidine (diastereomers) Example 241A were initially charged in dichloromethane (2 l) and cooled to 0° C. 42.85 ml (342.5 mmol) of trimethylsilyl cyanide and 42.1 ml (342.5 mmol) of boron trifluoride/diethyl ether complex were added slowly and the mixture was stirred at RT for 16 h. The reaction solution was then poured into 1.5 l of saturated sodium bicarbonate solution. Another 400 g of sodium bicarbonate were then added, and the solution was adjusted to pH 10 with conc. aqueous sodium hydroxide solution. The aqueous solution was extracted three times with 500 ml of dichloromethane and the combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 56.8 g (96% of theory, 2 diastereomers) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>CC(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:39]2[CH2:38][CH2:37][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH2:41][CH2:40]2)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1N1CCN(CC(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)CC1
Yield: 89.9 %

Procedure:
To a compound of N1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide (600 mg, 1.74 mmol) in dry acetone (20 mL) was added anhydrous potassium carbonate (1.21 g, 8.78 mmol) and 1-(2-methoxyphenyl)piperazine (336 mg, 1.98 mmol). The reaction mixture was refluxed for 24 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. The potassium carbonate was then removed by suction filtration and the solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 6c (780 mg, 89% yield).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.C([BH3-])#[N:45].[Na+]>C(OCC)(=O)C>[NH2:45][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=3)([CH3:39])[CH3:38])=[CH:23][N:22]=2)[CH2:25][CH2:26]1
Reactant: [BH3-]C#N
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCC(=O)CC2)cc1-c1ccccc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCC(N)CC2)cc1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
To a solution of 752 mg (1.26 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 7 ml methanol 970 mg (12.6 mmol) ammonium acetate were added at room temperature. The mixture was stirred 5 minutes at this temperature, cooled to 0° C. and treated with 119 mg (1.89 mmol) sodium cyanoborohydride. The reaction mixture was allowed to slowly warm to room temperature during 5 h, followed by dilution with 20 ml ethyl acetate, washing with 10 ml brine and extraction with 20 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 480 mg (64%) of the title compound as a white foam.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[Cl:20])[CH:12]=2)=[O:10])[CH2:5]1.[CH3:21]N(C=O)C>>[CH3:21][O:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[Cl:20])[CH:12]=2)=[O:10])[CH2:5]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC(O)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
NaH (0.07 g, 1.3 mmol) was added to a solution of (+/−)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone (0.25 g, 0.88 mmol) in DMF (10 mL), at 0° C. The reaction mixture was allowed to stir for 20 min, and Mel (0.188 g, 1.33 mmol) was added dropwise. After 3 h the reaction was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a white solid (0.13 g, 50%). MS: 297/299 (MH+); HPLC Rf: 4.11 min; HPLC purity: 93%.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:12][C:13]([CH2:14][OH:15])=[C:5]3[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2].[Na].S(OC)(O[CH3:29])(=O)=O.O>O1CCCC1.C(OCC)C>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:12][C:13]([CH2:14][O:15][CH3:29])=[C:5]3[C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1c(-c2ccc(OC)cc2)c2c(CO)cc3cccc1n32
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(-c2ccc(OC)cc2)c2c(COC)cc3cccc1n32
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
1-Ethyl-3-hydroxymethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.40 g, 1.31 mmol) was dissolved in 15 ml of dry tetrahydrofuran under a nitrogen atmosphere. Sodium hydrode (50% in oil) (0.06 g, 1.3 mmol) was added, and stirring was continued for 1/2 hour. Dimethyl sulfate (0.283 g, 2.25 mmol) was added, and the mixture was stirred at room temperature for 1day. 15 ml of water was added dropwise, and ther eaction mixture was diluted with 25 ml of diethyl ether. The organic material was extracted into diethyl ether, and the combined organic layers was washed with brine and dried over magnesium sulfate. The solvent was evaporated to afford 0.3 g (70%) of 1-ethyl-3-methoxymethyl-2-(4-methyoxyphenyl)pyrrolo[2,1,5-cd]indolizine. HPLC (Eluent: 65% CH3CN isocratic, 35% buffer H3PO4 pH=3): Rt=23.75 min (94% purity). 1H-NMR (CDCl3 /CD3OD, 200 MHz) δ: 1.42 (t, 3H); 3.16 (q, 2H); 3.41 (s, 3H); 3.88 (s, 3H); 4.78 (s, 2H); 7.07 (d, 2H); 7.21 (s, 1H); 7.56-7.69 (m, 3H); 7.81-7.91 (m, 2H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: COCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
The resulting 1-acetamido-4-methoxymethoxy-2-nitro-benzene is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to afford 1-amino-4methoxymethoxy-2-nitrobenzene. This latter compound is treated in accordance with the first paragraph of Example VI to afford 1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethoxy-2-nitrobenzene. This latter compound is reduced in accordance with the iron reduction technique as set forth in the third paragraph of Example XIX to afford 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethoxybenzene. This latter compound is treated in accordance with the first paragraph of Example XVI to afford 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethoxybenzene.
Reaction SMILES: [NH4+]=S.C(O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([N+:13]([O-])=O)[CH:12]=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([F:17])([F:18])[F:19])=[C:11]([CH:12]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1C(F)(F)F
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)ccc1C(F)(F)F
Temperature: 75 °C

Procedure:
Aqueous ammonium sulfide (60 g., 52-60%) is added dropwise to a warm (75° C.), stirred ethanol solution of 5-chloro-2-trifluoromethylnitrobenzene (22.6 g., 0.1 mole) and the resulting mixture is heated for four hours at a heating bath temperature of 97° C. and then allowed to cool to room temperature. The reaction mixture is poured into water, and the organic product is extracted with diethyl ether. After washing and drying the ether solution, the ether is removed by evaporation to give 5-chloro-2-trifluoromethylaniline.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH3:10])([C:7]([OH:9])=O)[CH2:3]1.Cl.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17]N.O[N:29]1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1)[CH2:17][CH:3]1[C:2](=[CH2:1])[CH2:6][CH2:5][C:4]1([CH3:10])[C:7]([NH2:29])=[O:9]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C1CCC(C)(C(=O)O)C1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CCC(C)(C(N)=O)C1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 49.7 %

Procedure:
A solution of 3-methylene-1-methylcyclopentanecarboxylic acid, (600 mg, 4.28 mmol) 3,5-bis(trifluoromethyl)benzylamine hydrochloride (1.196 g, 4.28 mmol), 1-hydroxy-7-azabenzotriazole (583 mg, 4.28 mmol) and diisopropylethylamine (745 μL, 4.28 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.230 g, 0.168, 6.42 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with dichloromethane (40 mL) and washed with water (3×30 mL), brine (1×30 mL), dried (anhydrous sodium sulfate) and the solvent was evaporated under reduced pressure. The crude product was purified via mplc (Lobar Fertigsaule, LiChroprep, 40-63 μm, ethyl acetate/hexanes (1:4)) yielding 777.6 mg (49%) of pure product. 1H NMR (500 MHz, CDCl3) 7.79 (s, 1H), 7.70 (s, 2H), 6.19 (bs, 1H), 4.98 (bs, 1H), 4.92 (bs, 1H), 4.62 (dd, 15.6 Hz, 6.2 Hz, 1H), 4.54 (dd, 15.8 Hz, 6.0 Hz, 1H), 2.78 (bd, 15.8 Hz, 1H), 2.46 (m, 2H), 2.30 (bd, 15.8 Hz, 1H), 2.18 (m, 1H), 1.70 (m, 1H), 1.31 (s, 3H).