Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:35])[CH2:16][C:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:11][C@H:10]2[OH:36])=[O:7])=[C:4]([N+:39]([O-])=O)[CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[OH2:7].[NH2:39][C:4]1[CH:3]=[C:2]([F:1])[CH:38]=[CH:37][C:5]=1[C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:35])[CH2:16][C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:11][C@H:10]1[OH:36])=[O:7]
Reactant: [H][H]
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2ccc(F)cc2[N+](=O)[O-])[C@H](O)C1
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2ccc(F)cc2N)[C@H](O)C1
Product: O
Yield: 51.8 %

Procedure:
A mixture of 4 parts of trans-4-[(4-fluoro-2-nitrobenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry. The residue was taken up In acetonitrile. The organic layer was evaporated again and the residue was crystallized from a mixture of acetonitrile and a few drops of water. The product was filtered off and dried, yielding 1.93 parts (51.8%) of trans-4-[(2-amino-4-fluorobenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1piperidinebutanamide monohydrate; mp. 127.0° C. (compound 67).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32](SCC)=[N+:31]([CH2:37][CH3:38])[C:30]=2[CH:39]=1.C(N(CC)CC)C>CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:32][N:31]([CH2:37][CH3:38])[C:30]=2[CH:39]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CCSc1sc2ccc(Cl)cc2[n+]1CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1CS(=C2C(=O)N(c3ccccc3)NC2C)c2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01) was mixed with 4.3 g (0.01 mol) 5-chloro-2-ethylthio-3-ethylbenzothiazolium tosylate in 15 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 1 hour, then filtered and washed with methanol. After drying the yield was 2.20 g (59%), mp 161°-162.5° C., λmax=382 (ε=21,000).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1>>[CH3:13][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: OC1CCCNC1
Reactant: Cc1nnc(-c2ccc(Br)cc2)o1
Product: Cc1nnc(-c2ccc(N3CCCC(O)C3)cc2)o1
Yield: 36.9 %

Procedure:
1-(4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-3-ol (120 mg, 0.463 mmol, 37% yield) was synthesized as described in General Procedure B using 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole (300 mg, 1.255 mmol) and piperidin-3-ol (254 mg, 2.51 mmol). Anal. Calcd. for C14H17N3O2 m/z 259.3, found: 260.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54]O)[CH:49]=1>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:54][C:50]3[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: OCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccnc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12 %

Procedure:
1,4-Diethylazodicarboxylate (205 μL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 3-pyridylmethanol (243 μL) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then the resulting suspension is filtered. The crude product is purified by recrystallization from ethanol to afford 63 mg (12%) of the title compound as a white solid.
Reaction SMILES: [OH-].[Li+].C([O:11][CH:12]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[CH:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(=O)C1C=CC=CC=1.Cl>O1CCCC1.CO.O.O>[C:38]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][CH:12]([OH:11])[CH:13]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)cc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)cc1)C(O)CCc1ccc(-c2ccccc2)cc1
Yield: 101 %

Procedure:
Aqueous solution of lithium hydroxide (22 mg) was added to a solution of the compound (120 mg) obtained from Step 1 above, in tetrahydrofuran:methanol:water (3:1:1, 5 ml) and the reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue thus obtained was taken in distilled water, acidified with dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with distilled water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound (100 mg).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=1.[ClH:21]>>[ClH:21].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(C)=O)cc1
Agent: Cl
Product: Nc1ccc(OCCCCCC(=O)O)cc1
Temperature: 10 °C
Yield: 55.6 %

Procedure:
To a mixture of 6-(4-Acetylamino-phenoxy)-hexanoic acid methyl ester 65 (290 grams, 1.04 moles), in concentrated hydrochloric acid (7.12 Liter) was refluxed for 48 hours. Excess concentrated hydrochloric acid was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried give pure 66 (150 grams, 55.6%) as a brown powder. The melting point was found to be 155-160° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].ClC1C=CC=C(C(OO)=[O:32])C=1>CO>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1S(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
A mixture of 3-methylthio-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.2 g, Reference Example 15), meta-chloroperbenzoic acid (61 mg) and methanol (25 ml) was stirred at ambient temperature for 1 hour and then evaporated. The residue was triturated with ethyl acetate to give the title compound (0.17 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[O:17][CH:18]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)[CH2:19][CH2:20][CH2:21][N:22]1[CH2:29][CH:28]2[O:30][CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23]1>CC#N.C(Cl)(Cl)Cl>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH:18]([O:17][C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:19][CH2:20][CH2:21][N:22]2[CH2:29][CH:28]3[O:30][CH:24]([CH2:25][N:26]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:27]3)[CH2:23]2)=[CH:38][CH:37]=1)#[N:36]
Reactant: CCN=C=O
Reactant: COc1ccc(OC(CCCN2CC3CNCC(C2)O3)c2ccc(C#N)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCNC(=O)N1CC2CN(CCCC(Oc3ccc(OC)c(OC)c3)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of ethyl isocyanate (18.8 mg, 0.25 mmol) in MeCN (2 mL) was added, together with K2CO3 (34.5 mg, 0.25 mmol), to a solution of 4-[1-(3,4-dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (Preparation H; 109.4 mg, 0.25 mmol) in chloroform (0.5 mL). The reaction mixture was stirred at rt for 4 days before being added to a solid phase extraction plug (SiO2, 0.5 g). The plug was washed with CHCl3:MeCN (2.5 mL of 80:20), and the product was finally eluted with CHCl3:MeOH (3×2.5 mL of 95:5) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[OH:5]
Reactant: Brc1ccc2c(c1)OCO2
Reactant: COc1ccc(Br)c(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(C(O)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (50 ml) solution of 2-bromo-5-methoxybenzaldehyde (10 g) was added dropwise a THF (30 ml) solution of the Grignard reagent prepared from 5-Bromo-1,3-benzodioxole (11.2 g) and Mg (1.6 g). The mixture was stirred for 1 hour at room temperature and ammonium chloride solution was added therein, then extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated. The residue was purified with silica gel column (Hex/EA=3/1) to give (2-bromo-5-methoxyphenyl) (1,3-benzodioxol-5-yl)methanol as an oily substance (15 g). (2-bromo-5-methoxyphenyl)(1,3-benzodioxol-5-yl)methanol was dissolved in ether (300 ml) and n-BuLi(1.6M/Hex: 64 ml) was added dropwise at -78° C. The reaction mixture was stirred for 5 minutes at -78° C., then stirred for 1 hour at 0° C. To the mixture was added DMF (30 ml) and stirred for 1 hour at room temperature. To the reaction mixture was added water and extracted with ether. The extract was washed with water and dried with magnesium sulfate then concentrated under reduced pressure. The obtained residue was dissolved in toluene (250 ml) and maleimide (6 g) and p-toluenesulfonic acid monohydrate (1.0 g) were added thereto. The reaction mixture was refluxed for 20 hours and the separated solid was filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue was added concentrated hydrochloric acid and heated under reflux for 1 hour. The mixture was cooled to room temperature and the resultant yellow-brown solid was collected by suction and washed with water, then recrystalized with THF to give the entitled compound (5.4 g).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][C@@H:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11].O.O.C[N+]([O-:34])(C)C>C1COCC1.CCOCC>[CH2:10]([O:12][C@@H:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][OH:34])=[CH:24][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11]
Reactant: C[N+](C)(C)[O-]
Reactant: C=Cc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: B1C2CCCC1CCC2
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(CCO)cc1)OCC
Reaction time: 22 h
Yield: 60.9 %

Procedure:
9-BBN (3.0 mmol, 6 mL of a 0.5 M solution in hexanes) was added to a stirred solution of ethyl(2S)-2-ethoxy-3-(4-vinylphenyl)propanoate (0.37 g, 1.48 mmol) in dry THF under argon. The reaction mixture was stirred for 22 h under argon. Trimethylamine N-oxide dihydrate (0.60 g, 5.4 mmol) was added and the mixture was heated to reflux overnight and diluted with ether (50 mL). The organic layer was washed with brine (×3), dried (MgSO4), filtered, and evaporated. The crude product was purified by flash chromatography (silica, heptane/ethyl acetate 3:1) to give the title compound as an colorless oil (0.24 g, 62%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(SC)=CC=1.[C:19]1([CH:25]=[N+]=[N-])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.ClCCl>[C:19]1([CH:25]2[O:8][CH:1]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(SC)cc1
Solvent: ClCCl
Product: c1ccc(C2OC2c2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a mixture of rhodium (II) acetate (0.0021 g), dichloromethane (4 ml) and benzaldehyde (0.051 ml) was added 1-methoxy-4-methylthiobenzene (0.0036 ml). To this mixture was added, with stirring, a solution of phenyldiazomethane (1 mmol in tert-butylmethyl ether (8 ml)) over 19 hours. The reaction mixture was stirred or a further 5 hours after which the mixture was allowed to stand at room temperature for 2 days. The solvent was removed in vacuo and the residue chromatographed on silica using dichloromethane:hexane 2:3 as eluant. The title compound was obtained as a colourless oil (0.0713 g, 22.6% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:35])[S:21][C:22]=1[N:23]([C:28]([O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:29])[CH2:24][CH:25]1[CH2:27][CH2:26]1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[CH:32]1([CH2:31][O:30][C:28](=[O:29])[N:23]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:22]2[S:21][C:20]([CH3:35])=[N:19][C:18]=2[C:16](=[O:15])[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1nc(C)sc1N(CC1CC1)C(=O)OCC1CC1
Reactant: Cc1nccc(N)n1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nccc(NC(=O)c2nc(C)sc2N(CC2CC2)C(=O)OCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A solution of 2-methyl-4-amino-pyrimidine (0.184 g, 1.68 mmol) in 10 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 0.84 ml, 1.68 mmol). The mixture was stirred at room temperature for 1 h. 5-(Cyclopropylmethoxycarbonyl-(cyclopropylmethyl)-amino)-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.135 g, 0.40 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography with heptane/ethyl acetate 100:0→0:100 gradient to yield cyclopropylmethyl-[2-methyl-4-(2-methyl-pyrimidin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid cyclopropylmethyl ester (0.101 g, 63%) as a colourless oil, MS (ISP): m/e=402.5 (M+H+).
Reaction SMILES: F[C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.[Cu]I>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:2]2[C:3]([C:8]3[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([CH3:16])[N:9]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(N)cn1
Reactant: CSc1cc(-c2nccnc2F)nc(C)n1
Agent: [Cu]I
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nccnc2-c2cc(SC)nc(C)n2)cn1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A glass microwave reaction vessel was charged with 4-(3-fluoropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (21 mg, 0.089 mmol), 5-amino-2-methoxypyridine (0.022 mL, 0.178 mmol), copper(I) iodide (2 mg, 8.89 μmol) and N-ethyl-N-isopropylpropan-2-amine (22.97 mg, 0.178 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 24 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The crude product was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (14 mg, 0.041 mmol, 46.3% yield). 1H NMR (300 MHz, CDCl3) δ 12.20 (s, 1H); 8.42 (d, J=2.05 Hz, 1H); 8.22 (s, 1H); 8.18 (s, 1H); 8.09 (dd, J=8.92, 2.63 Hz, 1H); 8.02 (d, J=1.90 Hz, 1H); 6.79 (d, J=8.77 Hz, 1H); 3.95 (s, 3H); 2.78 (s, 3H); 2.63 (s, 3H). m/z (ESI, +ve ion) 341.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:8]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.[CH3:28][C:29](O)=O.[BH-](OC(C)=O)(OC(C)=O)O[C:34](C)=O.[Na+].[OH-].[Na+]>CC(C)=O>[CH3:34][CH:29]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[C:8]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:3][CH2:2]1)[CH3:28]
Reactant: FC(F)(F)c1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(=O)O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)N1CCC(c2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2-c2ccncc2)CC1
Reaction time: 120 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl]pyrazole (Example C-83) (300 mg, 0.7 mmol) in 50 mL of acetone was added 1 mL of AcOH and NaBH(OAc)3 (15 g, 70.8 mmol). The mixture was warmed to reflux and was stirred for 5 days. The reaction mixture was poured onto 100 mL of 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The extracts were combined and washed with brine (1×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford the title compound: MS (M+H): 415 (base peak).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.C([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:23][C:20]2[CH:19]=[CH:18][C:17]([NH2:16])=[CH:22][CH:21]=2)=[CH:19][CH:18]=1
Reactant: BrCCCCCCCCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: Nc1ccc(OCCCCCCCCCCOc2ccc(N)cc2)cc1

Procedure:
Tetrabutylammonium bromide was used as the phase transfer catalyst. It was added to the contents of the flask immediately following addition of the second portion of the 1,10-dibromodecane. The amount of catalyst was 0.50 grams, or 2.5 parts per hundred parts of 4-acetamidophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO.C(Cl)Cl>[NH4+:12].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][NH:34][CH3:33])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O-:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](CNC)N1C(=O)[C@@](C)(CC(=O)[O-])C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Product: [NH4+]
Reaction time: 4 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (201 mg, 0.434 mmol; Example 210 Step A) in DCE (3 mL) was added methylamine hydrochloride (117 mg, 1.736 mmol) followed by sodium triacetoxyborohydride (184 mg, 0.868 mmol). After 4 hours, the mixture was diluted with methanol and DCM, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20-100% ethylacetate/hexanes followed by 6:1:0.1 DCM:MeOH:NH4OH) to afford the title compound.
Reaction SMILES: [C:1]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([C:5]#[N:6])[CH3:4])#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[C:5]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH:8]=1)[CH:25]=[O:26])([C:1]#[N:2])[CH3:4])#[N:6]
Reactant: COc1ccc(C(C)(C#N)C#N)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C(C)(C#N)C#N)cc1C=O

Procedure:
This compound was prepared from Compound 36 in the same manner of Compound 2.
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21]C)[CH:19]=[CH:20][C:9]=3[C:8](=[O:23])[C:7]2=1.Cl.N1C=CC=CC=1>O>[OH:21][C:18]1[CH:19]=[CH:20][C:9]2[C:8](=[O:23])[C:7]3[C:6]4[C:14](=[CH:2][C:3]([C:24]#[N:25])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3c(Br)c(C#N)ccc3c1C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 160 °C
Reaction time: 28 h

Procedure:
4-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U5, 325 mg, 0.822 mmol) was added with pyridine hydrochloride salt (3.80 g, 32.89 mmol) and stirred at 160° C. for 28 hr. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and filtered. After concentration under reduced pressure, the title compound was obtained as a crude product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:30])[N:23]([CH3:31])[CH:22]=2)[C:12]1=[O:32])=[O:5])C.O.[OH-].[Li+].C(O)(=O)C>CO.O>[CH3:31][N:23]1[C:24]2[C:29](=[C:28]([CH3:30])[CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([C:7]3[CH2:8][CH2:9][CH2:10][C:6]=3[C:4]([OH:5])=[O:3])[C:12]2=[O:32])=[CH:22]1
Reactant: CCOC(=O)C1=C(n2c(=O)n(Cc3cn(C)c4cccc(C)c34)c3ccccc32)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1cccc2c1c(Cn1c(=O)n(C3=C(C(=O)O)CCC3)c3ccccc31)cn2C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A solution of 120 mg (0.28 mmol) of 2-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclopent-1-enecarboxylic acid ethyl ester and 23 mg (0.56 mmol, 2.0 eq.) of lithium hydroxide monohydrate in 5 mL of methanol and 1 mL of water was stirred at room temperature for 2.5 days. Then the pH of the resulting mixture was adjusted to 3 with acetic acid and diluted with water. The precipitate was collected and washed with water. The isolated light pink solid was pumped overnight to give 94 mg (84%) of 2-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclopent-1-enecarboxylic acid as a light pink solid.