Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23](C#N)=[CH:22][CH:21]=3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[N-]=[N+]=[N-].[Na+].[Cl-].C([NH+](CC)CC)C.Cl.[NH:47]1[CH:51]=[N:50][N:49]=[N:48]1>C1(C)C=CC=CC=1.C(OCC)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([C:51]4[N:47]=[N:48][NH:49][N:50]=4)[CH:25]=3)(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(S(=O)(=O)Nc3ccc(C#N)cc3)cc2)ccc(C(C)=O)c1O
Reactant: c1nnn[nH]1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCc1c(OCc2ccc(S(=O)(=O)Nc3cccc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
Combine 4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-N-(4-cyano-phenyl)-benzenesulfonamide (1.44 g, 3.10 mmol), sodium azide (2.02 g, 31.0 mmol) and triethyl ammonium chloride (4.27 g, 31.0 mmol) in toluene (10.3 mL) and heat to reflux for 2 hours. Cool to ambient temperature and add 1N hydrochloric acid (20 mL) and ethyl acetate (20 mL). Extract the aqueous phase with ethyl acetate (2×20 mL), dry (sodium sulfate) and condense under reduced pressure. Sonicate resulting red residue in diethyl ether for 1 hour, collect the title compound by filtration as a white solid (831 mg, 1.64 mmol): 1H NMR (DMSO-d6) δ 0.82 (t, 3H), 1.45 (m, 2H), 2.57 (m, 5H), 5.30 (s, 2H), 6.62 (d, 1H), 7.30 (m, 1H), 7.45 (t, 1H), 7.60 (m, 2H), 7.67 (m, 2H), 7.78 (d, 1H), 7.85 (m, 3H), 10.65 (s, 1H), 12.82 (s, 1H) tetrazole H not observed; MS (m/z): 506 (M−1). The following compounds are prepared essentially by the method of Example 8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:29](/[CH:30]=[CH:31]/[CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:44]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:29](/[CH:30]=[CH:31]/[CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1)(=[O:46])[CH3:45]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3ccc(Br)cc3)c(/C=C/CN3CCCCC3)c2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3c2/C=C/CN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of Example 41i.e. (E)-2-(4-bromophenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (553 mg, 0.954 mmol) in toluene (14 mL) was added tributyl(1-ethoxy-vinyl)tin (1.03 g, 2.86 mmol) and tetrakis(triphenylphosphine) palladium (O) (55 mg, 0.05 mmol). The mixture was degassed by bubbling nitrogen into it for 10 minutes and was then heated to 120° C. for 4 h. The mixture was allowed to cool to room temperature and concentrated to a residue and dissolved in THF (12 mL). 1N HCl (3 mL) was added and the mixture was stirred at room temperature for 1 h. Sodium bicarbonate was slowly added until pH was reached 8-9 and the mixture was extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine, filtered and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 74 %

Procedure:
Preparation of example 53 from the title compound of Example 7 (hydrochloride) (31 mg, 0.10 mmol), (S)-2-tert-Butoxycarbonylamino-4-phenyl-butyric acid (34 mg, 0.12 mmol), triethylamine (0.021 mL, 0.15 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography, (5:4:1 hexane:CH2Cl2:methanol), also in an analogous manner, afforded the title compound (40 mg, 0.074 mmol) as a yellow powder in 74% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[CH:6][C:5]=1[F:22].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:12]=2[CH3:21])[CH:7]=[CH:6][C:5]=1[F:22]
Reactant: CCn1cc(Br)cn1
Reactant: COC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)ccc1F
Product: CCn1cc(-n2c(C)c(Sc3ccc(F)c(C(=O)OC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:36])[CH2:21][C:22]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([F:35])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.CO.[OH-].[Li+]>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:36])[CH2:21][C:22]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:35])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of methyl 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoate (70 mg, 0.14 mmol) in THF (2 mL) and methanol (2 mL), lithium hydroxide (2M, 2 mL) was added. After stirring at room temperature for 16 h, the mixture pH was adjusted to 2-3 with HCl (2 M) and extracted by ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (30%-40% CH3CN in 0.1% HCOOH) to afford target compound (35 mg, 53%) as a white solid. LCMS (ESI): m/z: 473.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12OCCC[O:22]1)(=[O:11])=[O:10].Cl[CH2:28][C:29]1([C:34]#[N:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:28][C:29]4([CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:34][N:35]=[C:16]3[C:15](=[O:22])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: N#CC1(CCl)CCCC1
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCCC3)CN12

Procedure:
The title compound was prepared as a yellow solid from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 416[M−H]. m.p.: 171.2-171.9° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][C:15]1[C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]3[N:28]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:29]=[CH:30][C:23]=23)=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C.O>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:34]2[CH2:33][CH2:32][CH:31]([N:28]3[C:24]4=[N:25][CH:26]=[N:27][C:22]([O:21][C:20]5[C:15]([CH3:14])=[N:16][CH:17]=[CH:18][CH:19]=5)=[C:23]4[CH:30]=[N:29]3)[CH2:36][CH2:35]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
4-Nitrophenyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 268 mg, 1.33 mmol) was added in three portions to a cooled (˜0° C.) solution of 4-(2-methyl-pyridin-3-yloxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 28; 275 mg, 0.89 mmol), and diisopropylethylamine (390 μL, 2.2 mmol) in anhydrous dichloromethane (10 mL). The mixture was warmed to room temperature and stirred for 1 h. Water (10 mL) was added, the layers were separated and the organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a 23 g Supelco column, eluting with 0-7% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 4-nitro-phenyl ester (180 mg, 43%) as a white foam.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.I.[OH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Agent: Cl
Agent: I
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 99 g (0.379 mole) of diphenyl-4-pyridyl-methanol, 50 ml of conc. hydrochloric acid, 200 ml of 57% hydroiodic acid and 200 ml of glacial acetic acid was refluxed for 41/2 hr and then was stirred at room temperature for 12 hr. The reaction mixture was poured over ice and was made basic with 50% sodium hydroxide. An aqueous solution of sodium thiosulfate was added, and the mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized from a mixture of methylene chloride-ether-hexane to give two crops of crystalline solids: Crop I, 40.87 g (44.0%), m.p. 124-126; Crop II, 25.38 g (27.3%), m.p. 123-125. Analysis of the mixture of the Crops I and II was as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[O:31]([C:33]#[N:34])[K]>C(O)(=O)C>[C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:31])[NH2:34]
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: N#CO[K]
Solvent: CC(=O)O
Product: NC(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml acetic acid, 14 mg KOCN were added at RT and stirred over night. After removal of the solvent under reduced pressure the residue directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:20][CH:19]2[CH2:21][CH:11]([CH2:12][C:13]3[C:14]([O:22][CH3:23])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[CH3:23][O:22][C:14]1[C:13]2[CH2:12][CH:11]3[CH2:21][CH:19]([CH2:20][NH:9][CH2:10]3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2c1CC1CC2CN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: COc1cccc2c1CC1CNCC2C1
Yield: 77.8 %

Procedure:
11-Benzyl-6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene hydrochloride (525 mg, 1.64 mmol), ammonium formate (2.07 g, 32.0 mmol and 10% palladium hydroxide on carbon (Pd(OH)2/C) (200 mg) were combined in MeOH (30 mL) and refluxed for 2 hours. The mixture was filtered hot through Celite and the filtrate concentrated then azeotroped from MeOH (5×50 mL) to yield a solid. This was recrystallized from MeOH/Et2O to provide a white solid (306 mg, 81%). 1H NMR (free base, CDCl3) δ 7.15 (t, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 3.82 (s 3H), 3.34 (br d, J=13.0 Hz, 1H), 3.11-3.02 (m, 4H), 2.94 (AB d, J=18.3 Hz, 1H), 2.87 (AB dd, J=18.3, 6.5 Hz, 1H), 2.41 (br s, 1H), 1.91 (AB q, 2H). GSMS m/e 203 (M+). mp 272-274° C.
Reaction SMILES: [I-].[F:2][C:3]([F:40])([F:39])[C:4]1[CH:5]=[C:6]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:7][N:8]([CH3:31])[C:9]([C:11]1[N:21]([CH3:22])[C:20](=[O:23])[C:14]2=[N+:15]([CH3:19])[CH:16]=[CH:17][CH:18]=[C:13]2[C:12]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:10].[OH-:41].[Na+]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C1COCC1>[F:40][C:3]([F:2])([F:39])[C:4]1[CH:5]=[C:6]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=1)[CH2:7][N:8]([CH3:31])[C:9]([C:11]1[N:21]([CH3:22])[C:20](=[O:23])[C:14]2[N:15]([CH3:19])[C:16](=[O:41])[CH:17]=[CH:18][C:13]=2[C:12]=1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[O:10]
Reactant: [OH-]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ccc[n+](C)c2c(=O)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ccc(=O)n(C)c2c(=O)n1C
Reaction time: 15 h

Procedure:
A mixture of 6-[N-[3,5-bis(trifluoromethyl)benzyl]-N-methylaminocarbonyl]-5-(4-fluorophenyl)-7,8-dihydro-1,7-dimethyl-8-oxopyrido[3,4-b]pyridinium iodide (Example 29) (100 mg), THF (3 ml), potassium ferricyanide (500 mg) and 1N-NaOH was stirred for 15 hours. The solvent was distilled off. To the residue was added ethyl acetate, and the mixture was washed with water and dried, then the solvent was distilled off. The residue was subjected to a silica-gel column chromatography (ethyl acetate) for separation and purification to afford the above-titled compound as colorless crystals (35 mg), m.p.210°-212° C. (recrystallized from ethyl acetate-isopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[N:10]([CH:17]3[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[C:14](O)=[O:15])=[CH:4][CH:3]=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[N:10]([CH:17]4[CH2:19][CH2:18]4)[CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)ccn2C2CC2)cn(C)c1=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(N2C(=O)c3ccn(C4CC4)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
1-Chloro-N,N-2-trimethyl-1-propenylamine (0.899 mL, 6.80 mmol) was added to a solution of 2-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylic acid (Step 240.3) (2 g, 4.86 mmol) in CH2Cl2 (40 mL) at 5° C. The reaction mixture was stirred at RT for 30 min, diluted in CH2Cl2 and a saturated aqueous solution of sodium bicarbonate, and extracted twice with CH2Cl2. The combined organic extracts were washed with water and brine, dried (Na2SO4), and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 95:5) to afford a red foam. This foam was refluxed in Et2O for 3 hrs. The title compound (1.35 g, 70.6% yield) was collected by filtration and obtained as an off-white solid. tR: 0.95 min (LC-MS 6); ESI-MS: 394.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 95:5): Rf=0.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.P(Br)(Br)[Br:12].C(=O)([O-])O.[Na+]>C(OCC)C>[Br:12][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of the above product 1-(4-chlorophenyl)ethanol in 100 ml of diethyl ether was slowly added a solution of 13.5 g (50 mmoles) of phosphorus tribromide in 50 ml of diethyl ether. The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into ice water. Sodium hydrogencarbonate was added to the resulting solution for neutralization, and the organic layer was extracted with diethyl ether. The organic layer was collected, washed with water, dried over anhydrous sodium sulfate and concentrated in a vacuum, giving 9.00 g (41 mmoles, 82% in yield) of 1-(1-bromoethyl)-4-chlorobenzene [1H-NMR (300 MHz, CDCl3) 2.02 (d, J=6.9 Hz, 3H), 5.1 (q, J=6.9 Hz, 1H), 7.26-7.40 (m, 4H)] in a nearly pure form.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:15][O:16][CH2:17][C:18](O)=[O:19].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:15][O:16][CH2:17][C:18]([NH:7][C:6]1[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:19]
Reactant: COCC(=O)O
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
Stir the mixture of 3-nitro-5-(trifluoromethyl)aniline (500 mg, 2.4 mmol), 2-methoxyacetic acid (220 mg, 2.4 mmol), 1-hydroxybenzotriazole (HOBt, 324 mg, 2.4 mmol), N-methyl morpholine (NMM, 480 mg, 4.8 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 920 mg, 4.8 mmol) in DMF (8 mL) at 80° C. for 16 hrs. Cool the reaction mixture to room temperature, add water (100 mL), extract with ethyl acetate (30 mL×2), combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=15:85) to yield the target compound (260 mg, 39%).
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]([OH:7])[CH2:2]1.[C:9]([O:13][C:14](=[O:17])[CH2:15]Br)([CH3:12])([CH3:11])[CH3:10]>C1COCC1.ClCCl>[C:9]([O:13][C:14](=[O:17])[CH2:15][O:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:1]([OH:8])[CH2:2]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O[C@H]1CCC[C@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 5.0 g (43 mmol) of cis/trans-1,3-cyclohexanediol (approx. 1.2:1 cis/trans mixture) in 20 ml of absolute THF and, at RT, add 24.8 ml (approx. 49.5 mmol) of phosphazene base P2-t-Bu in THF (approx. 2 M solution) dropwise. Stir the solution at RT for a further 30 min and then add dropwise to a mixture of 9.5 ml (64.6 mmol) of bromoacetic acid tert-butyl ester and add 10 ml of THF dropwise. Stir the mixture at RT overnight, then dilute with dichloromethane, and wash the organic phase successively with 1N hydrochloric acid, buffer solution (pH 7) and sodium chloride solution, dry over sodium sulphate and concentrate under reduced pressure. Separate the crude product by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1→1:1). 2.73 g (27.6% of theory) of the cis-configured target compound are isolated as a pure fraction.
Reaction SMILES: [OH-].[Na+].[C:3]1([N:9]2[C:17]3[N:16]=[CH:15][NH:14][C:13]=3[C:12](=[O:18])[NH:11][C:10]2=[O:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.CO>[CH2:20]([N:14]1[C:13]2[C:12](=[O:18])[NH:11][C:10](=[O:19])[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:17]=2[N:16]=[CH:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 0.53 g (13.2 mmol) of sodium hydroxide in 5.3 ml of water was added to a suspension of 3.0 g (13.2 mmol) of 3-phenylxanthine in 18 ml of methanol and the mixture was stirred at 70° C. for 1 hour. It was then treated dropwise with 1.56 ml (13.2 mmol) of benzyl bromide and stirred at 70° C. for 7 hours, the precipitate was filtered off with suction after cooling, washed with water and dissolved in 50 ml of 1 N sodium hydroxide solution, insoluble matter was filtered off and the solution was adjusted to pH 8-9 using 4 N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and purified by flash chromatography on a silica gel column, dichloromethane/methanol (79/1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[OH:8][CH2:7][C@@H:5]([NH:6][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
(S. Bhatia and J. Hajdu, Tetrahedron Lett. 1998, 29, 31-34). To a solution of D-serine methyl ester hydrochloride (20.00 g, 0.13 mol) and Et3N (35.82 mL, 0.26 mol) in CH2Cl2 (80 mL) at 0° C., was added in one portion a solution of TrCl (36.53 g, 0.13 mol) in CH2Cl2 (80 mL). The mixture was allowed to stir at 0° C. (24 h) under Ar and then successively washed with 10% aqueous citric acid (120 mL) and saturated aqueous brine (120 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to yield 45.20 g (97%) of crude desired product as a pale yellow crystalline solid. The product was used for next step without further purification: Rf=0.50 (1/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.29 (br s, 1H), 2.98 (br s, 1H), 3.29 (s, OCH3), 3.51-3.60 (m, CHH′OH, CH), 3.64-3.74 (m, CHH′OH), 7.16-7.30 (m, 9 PhH), 7.47-7.50 (m, 6 PhH).