Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:49][C@H:50]([C:58]([CH:60]1[C:67]2([NH2:69])[CH2:68][CH:63]3[CH2:64][CH:65]([CH2:70][C:61]1([C:71]([O:73][CH3:74])=[O:72])[CH2:62]3)[CH2:66]2)=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CN(C)CCN>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:49][C@H:50]([C:58]([CH:60]1[C:67]2([NH2:69])[CH2:68][CH:63]3[CH2:64][CH:65]([CH2:70][C:61]1([C:71]([O:73][CH3:74])=[O:72])[CH2:62]3)[CH2:66]2)=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@@H](N)Cc1ccccc1)C2
Agent: CC(C)COC(=O)Cl
Agent: CN(C)CCN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
5.06 Grams of Boc-L-tyrosyl-D-methionyl-glycine is dissolved in 40 ml of dimethylformamide and 1.28 ml of N-methylmorpholine is added to the solution. The reaction mixture is cooled to -50° C. and 1.51 ml of isobutylchloroformate is added causing a precipitate to form. The reaction mixture is allowed to warm to -20° over a 15 minute period and 4.45 g of methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride is added followed immediately by 1.25 ml of N-methylmorpholine The gum which forms dissolves in about 45 minutes while warming to room temperature. The reaction mixture is allowed to stand for 1.5 hours at room temperature and is then stored at 5° C. for 3 days. The reaction mixture is warmed to room temperature, 1.0 ml of N,N-dimethylethylenediamine is added and the reaction mixture is stirred for 10 minutes. The dimethylformamide is removed under reduced pressure at 32° C. and the residue is dissolved in a mixture of 70 ml of water and 100 ml of ethyl acetate. The aqueous layer is separated and extracted once with ethyl acetate and the combined ethyl acetate solutions are washed three times with 70 ml of a 0.5 M solution of potassium bisulfate, once with 70 ml of water, two times with a 0.5 M solution of potassium carbonate, and three times with 70 ml of a 10% sodium sulfate solution, then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the crude product which is then purified by low pressure chromatography on silica gel to give methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR25##
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C>[C:6]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reaction time: 2 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide (70.0 mg, 0.158 mmol) was dissolved in THF (1.0 mL) and treated with a 1 M solution of TBAF in THF (0.16 mL, 0.16 mmol) at room temperature. The solution was stirred for 2 hours and then diluted with diethyl ether (10 mL) and quenched with water (10 mL). The aqueous layers were extracted with diethyl ether (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2ncc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cn2ncc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of methyl 4-{[7-({3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (25 mg) in a mixed solvent of tetrahydrofuran/methanol (1:1, 1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 1N aqueous hydrochloric acid solution (0.5 mL) and water (1 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The resultant solid was collected by filtration, and washed with diisopropyl ether and dried to give the title compound (16 mg) as pale-yellow crystals.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[C:14]([O:20][CH2:21][N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)[C:25]=2[CH:24]=[CH:23]1)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>[C:14]([O:20][CH2:21][N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([C:31]3[CH:32]=[N:33][N:34]([C@@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH:8]=[O:9])[CH:35]=3)[C:25]=2[CH:24]=[CH:23]1)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C/C=C/C1CCCC1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.8 %

Procedure:
A solution of (2E)-3-cyclopentylacrylaldehyde (28, 345 mg, 2.50 mmol, 5.0 equiv), (2R)-2-bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methylpyrrolidine ((R)-35, 16 mg, 0.025 mmol, 0.05 equiv) and 4-nitrobenzoic acid (4.3 mg, 0.025 mmol, 0.05 equiv) in anhydrous chloroform (CHCl3, 2.0 mL, 25 mmol) was stirred at room temperature for 10 min before [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5, 0.150 g, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for 23 h. After LCMS showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by Combiflash with 0-80% EtOAc/hexane gradient elution to afford (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37, 169 mg, 211.8 mg theoretical, 80% yield) as a pale yellow foam. For (R)-37: C23H29N5O3 (MW, 423.51), LCMS (EI) m/e 424 (M++H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.[Cl:34][C:35]1[CH:36]=[C:37]([O:46][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1>>[Cl:34][C:35]1[CH:36]=[C:37]([OH:46])[CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C@@H:43]([OH:44])[CH2:45][NH:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH2:10][CH2:11]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)c(Cl)c1)(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCc3cc(F)ccc3F)cc2)CC1
Solvent: O=CO
Product: O=C(NCc1cc(F)ccc1F)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3Cl)CC2)cc1
Yield: 19.7 %

Procedure:
N-(4-{[4-(aminomethyl)-1-piperidinyl]sulfonyl}phenyl)-N′-(2,5-difluorobenzyl)urea formate (0.827 g, 1.72 mmol) was reacted with t-butyl(diphenyl)silyl 3-chloro-4-[(2S)oxiranylmethoxy]phenyl ether (0.516 9,1.17 mmol) according to example 37 to give the title compound (0.15 g, 0.23 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]([O:18][C:16]([NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCNCC1
Yield: 99.9 %

Procedure:
A solution of 1-benzyl-4-tertbutyloxycarbonylaminomethylpiperidine 8 (4.79 g; 15.7 mmol) in 120 ml of MeOH is poured into a hydrogenation reactor. The 10% Pd/C-based catalyst is added (0.872 g; 0.82 mmol) and the mixture is subjected to a hydrogen pressure of 3.5 bars (50 psi) for 24 hours in a Parr type shaker. After filtration on celite and washing with methanol, the medium is concentrated in order to produce 3.36 g (Yield=100%) of product in the form of white crystals.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[NH:8]2.Cl.CN(C)CCCN=C=NCC.[CH3:27][N:28]1[C:33](=[O:34])[CH:32]=[C:31]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:30]=[C:29]1[CH2:41][C:42]([O-])=[O:43].[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[N:8]2[C:42](=[O:43])[CH2:41][C:29]1[N:28]([CH3:27])[C:33](=[O:34])[CH:32]=[C:31]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:30]=1
Reactant: CC1Cc2c(cccc2OC(F)F)N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2c(OC(F)F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
125 mg of 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole [reference example 11d] and 193 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 242 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 4d) in 6 ml of N,N-dimethylformamide and 6 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then 25 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with a 0.1N hydrochloric acid solution, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (90/10: v/v), so as to give 170 mg of 2-{2-[4-(difluoromethoxy)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:44])[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][N:33]2C(=O)C3C(=CC=CC=3)C2=O)[CH:17]=[CH:18][CH:19]=1.O.NN.C(O)C>>[NH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)=[O:44]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN3C(=O)c4ccccc4C3=O)c2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN)c2)C1
Temperature: 25 °C

Procedure:
Into a 100-mL round-bottom flask, was placed N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanamide (870.0 mg, 1.36 mmol, 1.00 equiv) and 1M hydrazine monohydrate in ethanol (30.0 mL, 30.0 mmol). The resulting solution was heated at reflux for 1 hour. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residual solution was diluted with 30 mL of water and then extracted with 3×50 mL of DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (100˜50:1˜10:1˜1:1). This resulted in 600 mg (85%) of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)propanamide as a pale yellow syrup.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[CH3:11][O:12][CH2:13][C:14]#[C:15][C:16]1[C:21]2[CH:22]=[CH:23][O:24][C:20]=2[C:19]([NH2:25])=[CH:18][CH:17]=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH2:40][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[C:50]#[N:51]>CN(C=O)C>[C:50]([C:28]1[CH:29]=[N:30][C:31]2[C:36]([C:27]=1[NH:25][C:19]1[C:20]3[O:24][CH:23]=[CH:22][C:21]=3[C:16]([C:15]#[C:14][CH2:13][O:12][CH3:11])=[CH:17][CH:18]=1)=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]1)[CH:32]=2)#[N:51]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Reactant: COCC#Cc1ccc(N)c2occc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCN(C)CC4)c(OC)cc23)c2occc12
Temperature: 0 °C

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 0.63 ml) was added to a mixture of [4-(3-methoxyprop-1-ynyl)benzofuran-7-yl]amine (0.06 g) and 4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline (0.106 g) in DMF (5 ml) that was cooled to 0° C. The resultant mixture was stirred and allowed to warm to ambient temperature for 16 hours. The reaction mixture was reduced in vacuo and partitioned between ethylacetate and water. The organics were washed with water, saturated brine and dried with magnesium sulfate. The solvent was removed in vacuo and the residue purified by column chromatography on silica using a gradient of 0–10% methanol/dichloromethane as eluent. The product fractions were combined and reduced in vacuo and the residue dissolved in minimal dichloromethane, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0M ethereal HCl. The resultant solid was centrifuged and washed with diethyl ether (X3) and dried to give the title compound as a yellow solid. (0.077 g); NMR Spectrum: (DMSOd6 @ 373K) 2.30 (m, 2H), 2.80 (s, 3H), 3.15–3.20 (m, 2H), 3.36–3.50 (m, 11H), 4.02 (s, 3H), 4.37 (t, 2H), 4.45 (s, 2H), 7.01 (s, 1H), 7.35 (d, 1H), 7.44 (d, 1H), 7.59 (s, 1H), 8.00 (s, 1H), 8.11 (s, 1H), 8.65 (s, 1H); Mass Spectrum: M+H+ 540.14.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[I-].[Na+].[C:34](=[O:37])([O-])[O-:35].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([O:13][CH:14]([O:35][C:34](=[O:37])[C:25]([CH3:30])([CH3:26])[CH3:24])[CH:15]([CH3:23])[CH3:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(OC(=O)C(C)(C)C)C(C)C)n1Cc1cccc2c1ccn2-c1ccccc1C#N

Procedure:
A mixture containing 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5-carboxylic acid (550 mg, 1.27 mmol, prepared as described in part C of Example 9), the title A compound (979 mg, 5.08 mmol), sodium iodide (381 mg, 2.54 mmol) and cesium carbonate (1.86 g, 5.72 mmol) in 2.5 mL of dimethylformamide was heated at 60° C. for 7 hours in a stoppered flask. Upon cooling the reaction mixture was diluted with 110 mL of ethyl acetate and filtered. The organic extract was rinsed with three 15 mL portions of pH 4 buffer, 20 mL of 1:1, water:brine and 30 mL of brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1.3 g of crude product. Chromatography on 75 g of silica gel eluted with 4:1, hexanes:ethyl acetate yielded 567 mg of the title B compound.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[OH:24]>>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Product: COc1ccc(Oc2cn[nH]c(=O)c2)c(Cl)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and 2-chloro-4-methoxy-phenol afforded 5-(2-chloro-4-methoxy-phenoxy)-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of Intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-cyclohexyl-propionic acid methyl ester (Intermediate 12) which afforded the lithium salt of 2-[4-(2-chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid as a white solid (0.19 g); ES+-HRMS m/e calcd for C20H23N2O5Cl [M+H+] 407.1368, found 407.1369. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-1.19 (m, 6H), 1.44-1.65 (m, 4H), 1.65-1.77 (m, 1H), 1.93 (t, J=6.9 Hz, 2H), 3.81 (s, 3H), 5.09 (t, J=7.7 Hz, 1H), 5.52 (d, J=3.0 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.97 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10](C(=O)[C@@H]3CCCN3S(C3C=CC5C(=CC=CC=5)C=3)(=O)=O)[CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc([C@@H]2CNc3c(ccc4ccccc34)S2)cc1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
A mixture of (R)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (11.50 g, 0.019 mole), 86% potassium hydroxide (15.0 g, 0.227 mole) and ethanol-water (10:1, 230 ml) is refluxed under argon for one hour. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and saline, dried over sodium sulfate and distilled to remove the solvent. The residue is purified by silica gel column chromatography (CHCl3) and thereafter recrystallized from ethyl acetate-hexane to give (R)-(+)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (3.74 g, 63%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:11]1[CH2:10][CH:9]=[C:8]([CH2:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cc(CCC2CCCO2)ccn1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C1=C(CCC2CCCO2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-(2-[tetrahydrofuran-2-yl]ethyl)pyridine (3.0 g, 16.9 mmol) in anhydrous dimethylformamide (5 ml) was treated with benzyl bromide (2.2 ml, 18.6 mmol) and the mixture was stirred at room temperature for one hour. The reaction was diluted with absolute ethanol (100 ml), treated with sodium borohydride (0.8 g, 21.2 mmol) and stirred at reflux for one hour. The solvent was evaporated in vacuo and the residue partitioned between diethyl ether and water. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed with 3% methanol in dichloromethane as eluant to afford the title compound (3.75 g, 82%) as a colourless oil; δH (DMSO-d6) 1.30-2.08 (8H, m, 4×CH2), 2.45-2.52 (2H, m, tetrahydropyridinyl CH2), 2.52-2.56 (2H, m, CH2), 2.60-2.66 (2H, m, tetrahydropyridinyl CH2), 3.50 (2H, s, PhCH2N), 3.52-3.80 (3H, m, tetrahydrofuranyl CH2 and CH), 5.50-5.55 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.34 (5H, m, ArH); m/z (CI+, NH3) 272 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24]C)[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 79.5 %

Procedure:
A mixture of 2.66 gm (8.0 mMol) 1-benzyl-4-(6-methoxynaphth-2-yl)piperidine and 2.3 mL (20 mMol) 48% hydrobromic acid in 15 mL acetic acid was stirred at reflux for about 18 hours. The reaction mixture was cooled and then neutralized by the addition of 5N sodium hydroxide. The mixture was extracted well with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in a mixture of hexane and ethyl acetate and this suspension was subjected to sonication. The suspension was then filtered to provide 2.02 gm (79%) of the desired compound as a tan solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: C1CN(C2CNC2)CCO1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
tert-butyl 3-morpholinoazetidine-1-carboxylate (31 mg) was treated with 4N HCl in dioxane (5 eq) in 1 mL of DCM. The reaction mixture was stirred for 3 hours at room temperature and then concentrated to dryness to yield 4-(azetidin-3-yl)morpholine in quantitative yield. 4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.413 g) was reacted with 4-(azetidin-3-yl)morpholine via General Procedure B to afford 0.4 g 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine