Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C([Cl:8])=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=1)[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[ClH:8].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N-:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=1)[C:13]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)=[O:14]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCC(C(=O)c2cccc([N-]c3ccco3)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
2-Furoyl chloride (0.15 ml, 1.5 mmol) was added to a solution of 4-[3-aminobenzoyl]-1-methylpiperidine (257 mg, 1.2 mmol) and triethylamine (0.2 ml, 1.4 mmol) in tetrahydrofuran (10 ml). The reaction mixture was stirred 2 h at room temperature. The reaction mixture was diluted with ethyl acetate and 1N sodium hydroxide then extracted with ethyl acetate. The ethyl acetate extracts were washed with 1N sodium hydroxide, water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give 440 mg. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:5:0.5) gave 350 mg (95%) of a foam. Crystallization as the hydrochloric acid salt from ethyl acetate/ethanol provided 320 mg of a yellow powder with mp>200° C. MS(m/e): 313(M+1), 311(M−1).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=[C:3]1[C:18]([O:20]CC)=[O:19].Cl>C(O)(=O)C>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1nc2cccnc2n(-c2ccccc2)c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1nc2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
10.74 g (36 mmol) of ethyl 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate was dissolved in acetic acid (270 mL), and 6 N hydrochloric acid (80 mL) was added thereto at room temperature. Then, the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and water (100 mL) was added. The solid thus obtained was separated by filtration and dried, to obtain 6.50 g (yield: 67%) of 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid as pale brown crystals.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:6])[CH:4]=[CH2:5].[Br:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[CH3:1][N:2]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][Br:11])[C:3](=[O:6])[CH:4]=[CH2:5]
Reactant: C=CC(=O)N(C)[Si](C)(C)C
Reactant: O=C(Cl)CCCBr
Product: C=CC(=O)N(C)C(=O)CCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
In a nitrogen glove bag 7.27 g (0.05 mole) of N-methyl-N-trimethylsilylacrylamide was placed in a one-necked flask. The flask was fitted with an additional funnel topped with a drying tube. With the flask contents cooled to ice/water temperatures, 9.28 g (0.05 mole) of 4-bromobutyryl chloride was added dropwise through a dropping funnel to the flask over a period of half an hour. The resulting yellow clear mixture was stirred for an additional two hours. The disappearance of the acyl chloride carbonyl band (1800 cm-1) and the increase in intensity of the product amide band (1670 cm-1) was monitored by IR. The by-product trimethylsilyl chloride was removed in vacuo to give 13 g of product. It was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C@@:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[OH:3].S(Cl)(Cl)=O.[CH3:17]O>>[C:1]([O:12][CH3:17])(=[O:11])[C@@:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:4])[OH:3]
Reactant: CO
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@](C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g (6.0 mmol) of (S)-atrolactic acid in 7 mL of methanol was cooled in an ice-water bath and stirred while 0.70 mL (1.15 g, 9.6 mmol) of thionyl chloride was added dropwise. The resulting mixture was stirred at room temperature for one hour, then concentrated under reduced pressure to give 1.1 g of methyl (S)-atrolactate, nD 25 1.5096.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[C:32](Cl)(=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)CC)C.[NH2:52][CH2:53][C:54]([CH3:57])([OH:56])[CH3:55]>ClCCl>[F:26][C:24]([F:27])([F:25])[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:32]([NH:52][CH2:53][C:54]([OH:56])([CH3:57])[CH3:55])=[O:33])[CH:31]=[CH:30][CH:29]=3)[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)([OH:28])[C:20]([F:21])([F:22])[F:23]
Reactant: CC(C)(O)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC(=O)Nc1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a stirred solution of 2-(4-((4-(3-aminophenoxy)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.115 mmol, 500 mg) in dichloromethane was added 4-nitrophenyl carbonochloridate (1.115 mmol, 225 mg) followed by triethylamine (1.115 mmol, 155 μl, 113 mg). The reaction was stirred for 30 minutes then 1-amino-2-methylpropan-2-ol (2.230 mmol, 199 mg) was added. The reaction was stirred for 2 hours then was chromatographed on silica (eluting with a gradient of dichloromethane to dichloromethane/methanol (8%)) to give the title compound (300 mg). MS (ESI) m/z 564.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:42]3[CH2:41][CH2:40][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:44][CH2:43]3)=[O:14])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.2 g, 0.719 mmol) in 10 mL of DCM was taken, EDCI.HCl (137 mg, 0.719 mmol) was added and stirred for 10 min at RT. N-Boc piperazine (133 mg, 0.719 mmol) was added to the reaction mixture and stirred for 24 h at RT. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated and purified by column chromatography (neutral alumina; 2% Methanol-DCM) then purified by reverse phase chromatography to afford 90 mg of tert-butyl 4-(2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetyl)piperazine-1-carboxylate.
Reaction SMILES: COC1N=C2C(=CC=1)N[C@@H](C)C[C@H]2NC(=O)C.[CH3:18][C@H:19]1[CH2:28][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[N:25]=2)[NH:20]1.Cl[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:41]([O:40][C:38]([N:20]1[C:21]2[C:26](=[N:25][C:24]([C:33]([F:34])([F:36])[F:35])=[CH:23][CH:22]=2)[C@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH2:28][C@@H:19]1[CH3:18])=[O:39])([CH3:43])[CH3:42]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N[C@@H]1C[C@H](C)Nc2ccc(C(F)(F)F)nc21
Agent: CN(C)c1ccccn1
Agent: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 68 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 46, Step 2, by replacing (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide, with (+/−)-cis-N-(2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (0.140.g, 0.512 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purify using silica gel column chromatography (gradient eluent, 0-5% MeOH in ethyl acetate) to provide the title compound (0.123 g, 68%). MS (ES+): 360 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]([OH:13])=O.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:11](=[O:13])[CH2:10][C:4]2[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c(Cl)cccc1Cl
Yield: 34.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,6-dichlorophenyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 119, (2S,4R)-4-benzyl-1-(2-(2,6-dichlorophenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (12.1 mg, 34.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.92 (s, 1H), 7.54-7.60 (m, 2H), 7.44 (d, 2H), 7.25-7.34 (m, 5H), 7.15-7.24 (m, 3H), 6.93-7.03 (m, 4H), 4.48-4.51 (m, 1H), 3.95 (m, 2H), 3.50-3.59 (m, 1H), 3.15 (m, 1H), 2.63-2.73 (m, 3H), 1.89-1.93 (m, 2H). MS (EI) for C32H27C12FN2O3. found 578.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: [H][H]
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccccn2)cc1N

Procedure:
A suspension of 20 g. (0.082 mol) of 2-(3-nitro-4-aminobenzoyl)pyridine in 1 liter of tetrahydrofuran containing 5 g. of 5% palladium on carbon was reduced with hydrogen under a pressure of 3 atmospheres. The resulting mixture was filtered and concentrated in vacuo to a reddish oil which was dissolved in a minimum amount of methylene chloride and diluted with petroleum ether to yield 2-(3,4-diaminobenzoyl)pyridine as a slightly unstable yellow solid, mp. 137° -138° C. (water).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>C(Cl)Cl>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N:20]1[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]1=[NH2+:22]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nn1cc(Cl)ccc1=[NH2+]
Reaction time: 0.33 h
Yield: 73 %

Procedure:
The fresh solution of O-(mesitylsulfonyl)hydroxylamine (2.14 g, 9.96 mmol, Eq: 1.00) in CH2Cl2 prepared in the previous step was added dropwise at 0° C. to a solution of 5-chloropyridin-2-amine (1.28 g, 9.96 mmol, Eq: 1.00) in CH2Cl2 (20 ml). The suspension was stirred for 20 min and then filtered. The residue was washed with DCM and dried under high vacuum to give the desired product as a white powder (2.5 g, 73%). MS m/z=144.03 (M−MsO+H+)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:34]1[NH2:42].C(N(CC)CC)C.C(O)CCC>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH:42][C@@H:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:41][C@@H:33]3[O:32][CH3:31])[CH:29]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Yield: 78.9 %

Procedure:
A mixture of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (260.0 mg, 0.0005494 mol), (1R,2S)-2-methoxyindan-1-amine (0.359 g, 0.00220 mol) and triethylamine (115 μL, 0.000824 mol) in 1-butanol (0.97 mL, 0.011 mol) was subjected to microwave irradiation (300 watts, 200° C.) for 30 minutes. The resulting dark brown mixture was filtered and concentrated. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to give 0.26 g (79%) of the title compound. LC/MS: Rt=3.42 min, ES+ 600 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: Cc1csc(S(=O)(=O)Cc2cc(Cl)nc(Cl)n2)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(S(=O)(=O)Cc2cc(N3CCOC[C@@H]3C)nc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a cooled (ice/water bath) solution of 2,4-dichloro-6-[(4-methyl-1,3-thiazol-2-yl)sulfonylmethyl]pyrimidine (901 mg, 2.78 mmol) in DCM (12 mL) was added triethylamine (0.45 mL, 3.23 mmol). The resulting solution was treated dropwise, over 3 minutes, with a solution of (3S)-3-methylmorpholine (319 mg, 3.15 mmol) in DCM (2.5 mL). The reaction mixture was stirred, under nitrogen for 24 hours, allowing reaction to warm to RT. Water (20 mL) was added to reaction mixture and stirred for 15 minutes. The organic layer was then separated, dried (MgSO4) and evaporated to give crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material (615 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=5[NH:23][C:22]4=[O:31])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2C[C@@H](CI)CO2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 1.74 g of cis-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 1.5 g of 1-(4-piperidyl)-5-chloro-benzimidazolin-2-one and 0.8 g of potassium carbonate in 20 ml of dimethylformamide is heated with stirring at 70° C. for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue is recrystallized from ethanol to give 1-[1-(cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]-5-chloro-benzimidazolin-2-one as colorless prisms, melting at 207.5°-208.5° C. The corresponding maleate melts at 207° C. with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:29]=1[O:30][CH2:31][C@H:32]1[O:37][CH2:36][C@@H:35]([CH2:38][OH:39])[N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33]1)=[O:26])[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:57](N2C=NC=C2)=[O:58])C=1.[F:64][C:65]([F:69])([F:68])[CH2:66][NH2:67]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:29]=1[O:30][CH2:31][C@H:32]1[O:37][CH2:36][C@@H:35]([CH2:38][O:39][C:57]([NH:67][CH2:66][C:65]([F:69])([F:68])[F:64])=[O:58])[N:34]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:33]1)=[O:26])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NCC(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Yield: 73.8 %

Procedure:
tert-butyl (2S,5R)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-(hydroxymethyl)morpholine-4-carboxylate (350 mg, 0.489 mmol) and CDI (159 mg, 0.978 mmol) in pyridine (4.89 mL) were heated to 60° C. for 30 min, LC/MS shows formation of desired intermediate. 2,2,2-trifluoroethylamine (1153 μl, 14.67 mmol) was then added and the reaction heated at 60° C. overnight (18 hours). LCMS shows complete conversion the next morning. The solvent was removed in vacuo and the residue was purified on silica gel (120 g), eluting with a gradient of 10-100% EtOAc/hexanes to afford the title compound (310 mg, 0.361 mmol, 74% yield) as a white foam, MS (ESI): m/z=841.4 (M+H); 98% pure by LC/MS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[S:34]([CH3:33])(=[O:36])=[O:35])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.05 h

Procedure:
N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 22) (0.50 g) was dissolved in DCM (10 ml) and cooled to 0-5° C. in an ice bath. Triethylamine (0.55 ml) was added followed by dropwise addition of methylsulphonyl chloride (0.11 ml) and the mixture was allowed to warm to ambient temperature over 2 hours. The solution was concentrated then the solid was dissolved in DCM (5 ml) and water (5 ml) was added. The solution was loaded onto a Varian Chem Elut column and after 3 minutes was washed through with DCM (20 ml). The DCM layer was then concentrated and the solid washed with ether and filtered to give the title compound (0.58 g) as a solid. NMR (CDCl3): 1.7 (s, 6H), 2.2 (s, 3H), 3.4 (s, 6H), 7.2 (s, 4H), 7.4 (d, 1H), 7.5 (d, 1H), 8.4 (d, 1H), 8.5 (d, 1H); MS (ESP−): 533; EA: found: C, 44.4; H, 4.5; N, 5.1%; C20H23ClN2O7S3 requires C, 44.9; H, 4.3; N, 5.2%.
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:13](Cl)(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=1>CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:13]([NH:1][NH2:2])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: CO
Product: NNS(=O)(=O)c1cccc2cccnc12
Temperature: 5 °C
Yield: 71.7 %

Procedure:
A 500 ml Erlenmeyer flask equipped with a magnetic stirrer and a thermometer is charged with 200 ml of methanol and 3.40 g (0.10 mol) of 95% hydrazine. The solution is cooled to 5° C, and 11.38 g (0.05 mol) of 8-quinolinesulfonyl chloride is added in small portions at a rate such that the reaction temperature does not exceed 15° C. After the reaction is complete, the solution is allowed to warm slowly to room temperature. The precipitating solid is filtered off to give 8.00 g of 8-quinolinesulfonyl hydrazine (C9H9N3O2S), m.p. 135°-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C.C(OCC)(=O)C>[CH3:18][N:17]1[C:16](=[O:19])[C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:22][CH2:23][CH2:24][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:7][CH:6]=1
Reactant: Cc1cccc2c(=O)n(C)c(-c3ccc(O)cc3)nc12
Reactant: ClCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2c(=O)n(C)c(-c3ccc(OCCCN4CCCCC4)cc3)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 8.6 %

Procedure:
2-(4-Hydroxyphenyl)-3,8-dimethyl-4(3H)-quinazolinone (500 mg, 1.88 mmol) was mixed with 1-chloro-3-bromopropane (326 mg, 2.07 mmol) and potassium carbonate (519 mg, 3.76 mmol) in DMF (5 ml), and stirred at 80° C. for 4 hours. After cooled to room temperature, potassium carbonate (519 mg, 3.76 mmol), potassium iodide (312 mg, 1.88 mmol) and piperidine (320 mg, 3.76 mmol) were added to the reaction solution, and further stirred at 80° C. for 12 hours. The reaction solution was diluted with ethyl acetate, then washed with aqueous 1 N sodium hydroxide solution and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=5/1) and recrystallized from ethyl acetate to obtain the intended compound (63 mg, 8.6%) as a colorless solid.